Grants and Awards

One-year period ending January 4, 2021. Click on a title to read more.
Awards information as defined in UW SAGE.
UCB Collaboration Amendment for Phase 1B.
Bacci, Jennifer Lynn , Department Of Pharmacy
Award Date: 12/16/2020
Sponsor: UCB Pharma, Inc. Amount: $55959
Abstract
This project seeks to develop and evaluate a community pharmacy-based population health intervention for people living with epilepsy.
Personnel
Bacci, Jennifer Lynn, Principal Investigator, Assistant Professor, DEPARTMENT OF PHARMACY • White, Harold Steve, Key Personnel, Professor, DEPARTMENT OF PHARMACY • ZARAA, SABRA, Other, Research Assistant (E S UAW ASE), DEPARTMENT OF PHARMACY • Stergachis, Andreas S, Co-Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
A Nanodrug for the Cure of Metastatic Breast Cancer .
FERRARI, MAURO , Pharmaceutics
Award Date: 12/14/2020
Sponsor: US Army Medical Research and Materiel Command (USAMRMC) Amount: $3221602.97
Abstract
The Objectives of this application are: 1) to complete GLP safety studies of iNPG-pDox in two animals species in support of an IND filing with the FDA; 2) to secure approval by the US FDA for clinical trials of iNPG-pDox for the treatment of TNBC with visceral metastasis; 3) to perform a Phase I clinical trial to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and other toxicities possibly associated with iNPG-pDox in patients with TNBC visceral metastasis; and 4) to conduct a Phase II clinical trial to evaluate the ORR, efficacy, and safety of iNPG-pDox in TNBC patients. Our central hypothesis is that iNPG-pDox will prove safe and provide long-term survival benefits (disease-free outcomes) in patients, where the drug is able to penetrate the relevant biological barriers and localize treatment on the metastatic lesions – resulting in a breakthrough treatment option for patients with few to no effective alternatives.
Personnel
Ferrari, Mauro, Principal Investigator, Affiliate Professor, PHARMACEUTICS • Ho, Rodney J.Y., Key Personnel, Professor, PHARMACEUTICS • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Deprey, Teresa M, Budget Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Deprey, Teresa M, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS
Computational Design of Orally Available Bioactive Peptides.
BHARDWAJ, GAURAV , Medicinal Chemistry
Award Date: 12/14/2020
Sponsor: Genentech, Inc. Amount: $95000
Abstract
The goal of this project is to design in silico peptides with useful pharmacokinetic properties, synthesize them and characterize their in vitro behavior. These peptides will be low molecular weight and therefore have the potential to be used by oral delivery. Iterative design will be used to optimize their properties.
Personnel
Bhardwaj, Gaurav, Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Rat and Canine Microphysiological Systems of the Kidney Proximal Tubule for Chemical Toxicity Screening.
Yeung, Catherine , Department Of Pharmacy
Award Date: 11/23/2020
Sponsor: Nortis, Inc Amount: $82939
Abstract
This project is a collaboration between Nortis Inc. (PI, T. Neumann) and the University of Washington School of Pharmacy (Co-Is, C. K. Yeung and E. J. Kelly). The goal of this application is to develop commercially viable kidney proximal tubule microphysiologic systems (KPT-MPS) using rat and canine proximal tubule epithelial cells (PTECs) that can be used in pre-clinical drug development to identify potential nephrotoxicity.
Personnel
Yeung, Catherine, Principal Investigator, Assistant Professor, DEPARTMENT OF PHARMACY • Zelnick, Leila, Key Personnel, Research Assistant Professor, DEPARTMENT OF MEDICINE • Van Ness, Kirk Peter, Key Personnel, RESEARCH SCIENTIST/ENGINEER 2, PCEUT - KELLY LAB, PHARMACEUTICS • Himmelfarb, Jonathan, Key Personnel, Professor, DEPARTMENT OF MEDICINE • Bammler, Theodor K., Key Personnel, RESEARCH SCIENTIST/ENGINEER-SENIOR, Enviro & Occup, ENVIRO & OCCUP HEALTH • Kelly, Edward J, Multiple PI, Associate Professor, PHARMACEUTICS • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Impact of anticholinergic and dopamine receptor blocking drug exposure on Parkinson Disease trajectory and outcomes.
GRAY, SHELLY L. , Department Of Pharmacy
Award Date: 11/16/2020
Sponsor: University of Pennsylvania Amount: $32998
Abstract
This application will examine how anticholinergic and antidopaminergic medication exposure relate to measured outcomes in Parkinson disease populations. Dr. Gray will be involved in all aspects of the study including study design, analysis, interpretation of findings, and manuscript preparation. My primary responsibility is to provide guidance on the measurement of medication exposure from Medicare claims data. This will entail bi-monthly meetings over the course of the study period.
Personnel
Gray, Shelly L., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Administrative Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, Budget Contact, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Kimura, Maya, eGC1 Preparer, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY
Effectiveness of Gastric Sleeve vs. Gastric Bypass for Cardiovascular Disease Y3.
BASU, ANIRBAN , Department Of Pharmacy
Award Date: 11/05/2020
Sponsor: Kaiser Permanente Amount: $91840
Abstract
Bariatric surgery is one of the most effective treatment strategies for weight loss in the severely obese. Currently, two operations constitute the majority of these procedures: Vertical Sleeve Gastrectomy (VSG), the newest restrictive procedure, in which only stomach size is reduced, and Roux-en-Y Gastric Bypass (RYGB), the ‘gold standard’ procedure, in which gastric capacity is similarly limited but with an additional modest bypass of a section of small intestine. From 2008-2011, there was a ~5-fold increase in use of VSG in North America (from 4% to 19%); in contrast, use of RYGB declined from 51% to 47%. If trends continue, VSG may comprise up to 50% or more of all bariatric procedures by 2020. The reasons for this dramatic shift in procedural preference are unknown, but it is likely due to the perception of surgeons that VSG and RYGB are at clinical equipoise, but VSG is easier to perform, less expensive, and has fewer complications. A clear evidence base to support these perceptions does not exist. Current clinical knowledge suffers from two major gaps. GAP 1: Very few studies have included many important cardiovascular health outcomes. Comparative changes with RYGB and VSG in prevalent cardiovascular disease (CVD) risk factors such as hypertension and dyslipidemia, as well as overall CVD risk, have not been studied. There is also almost nothing known about the comparative safety of VSG and RYGB beyond the standard reporting period of 30 days after surgery. GAP 2: Almost nothing has been published regarding the heterogeneity in comparative effectiveness and safety between these two procedures. Even among the few small published comparative studies, there is no understanding of how heterogeneity in effects might determine which procedure is most appropriate for certain kinds of patients. Our own preliminary work clearly shows that racial/ethnic minority patients have different weight loss responses to RYGB (losing less weight) but similar responses to VSG (no difference in weight loss), compared to whites. Given these major gaps in knowledge, large-scale comparative effectiveness studies, using real-world clinical populations are urgently needed to improve bariatric treatment decision-making for severely obese patients, especially with respect to CVD outcomes. We have designed such a study to compare the effectiveness of VSG and RYGB for hypertension, dyslipidemia, and diabetes remission as well as overall CVD risk reduction in more than 17,000 VSG and 11,000 RYGB patients, from a real-world health care setting with an integrated electronic medical record. This combined sample size is over 20 times the number of VSG and RYGB patients that have been directly compared in case series and controlled trials to date (n = 1,041). No other studies in the literature have the diversity of bariatric surgery patients in our sample, who are 56% Hispanic or non-Hispanic Black. We will apply innovative econometric techniques to deal with selection biases in observation data and study heterogeneity in effects to inform clinical knowledge and identify areas where further studies are needed. We have assembled an experienced, interdisciplinary research and clinical care team to address the following specific aims over a median three years of follow-up.
Personnel
Basu, Anirban, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kreuter, William I., Key Personnel, RESEARCH CONSULTANT, DEPARTMENT OF PHARMACY • Barthold, Douglas G., Key Personnel, Research Assistant Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Natural Product-Drug Interaction Research: The Roadmap to Best Practices.
THUMMEL, KENNETH E. , Pharmaceutics
Award Date: 11/05/2020
Sponsor: Washington State University (WSU) Amount: $441729
Abstract
Administrative Core The Administrative Core under the parent grant has a two-fold responsibility. At the program level, the Administrative Core coordinates the basic administrative and financial services to the Cores and participating institutions. At the project level, the Administrative Core is charged with 1) identifying a priority list of NPs that will be investigated for drug interaction liabilities, 2) designing appropriate in vitro and clinical interaction studies involving the selected NPs, 3) supporting the interaction projects by sourcing and ensuring quality of the NP study materials and by coordinating analysis of the pharmacokinetic samples generated from the interaction projects, and 4) disseminating the data generated from the interaction projects via a robust data repository and public-facing portal.The Administrative Core component of this subcontract supports the effort of Dr. Kenneth Thummel (Co-I). Dr. As a member of the Administrative Core and Steering Committee, Dr. Thummel will provide advice and counsel for all elements of the programmatic function of the Administrative Core, including execution of the Interaction Projects, development of new recommended approaches (RAs) and the dissemination of NaPDI research findings and evaluation of its impact on the research community.Pharmacology Core For the 5-year period of the parent grant, the Pharmacology Core has the principal responsibility of designing and implementing the Interaction Projects. The process begins with the selection of natural products (NPs) for investigation by the NaPDI team. This occurs in concert with input from the Steering Committee (representing leadership of all Cores and the NCCIH grant program officer). The list of NPs proposed in this grant application (kratom, hemp, goldenseal/echinacea, and black pepper) is the result of such interactions. The NP priority list will be updated regularly throughout the course of the grant, as described in our Research Strategy. NP selection is the product of an extensive literature review and, for kratom and hemp, carefully orchestrated preclinical studies that led to a definitive assessment of their risk or safety and the need for further investigation. Additional pre-clinical interaction studies of selected NPs will be performed by the Pharmacology Core team, as needed. Results will be evaluated using rigorous, predefined decision trees as guides, for determination of the need for a clinical NP-drug interaction study, and implemented, as described in the Research Strategy.The Pharmacology Core component of this UW subcontract supports the efforts of Dr. Allan Rettie (Co-I) and Dr. Jashvant Unadkat (Co-I), two preeminent translational pharmacologists, and their lab personnel. The two Co-I will work with the Pl of the parent grant, Dr. Mary Paine, in reassessing current priority natural products: kratom, hemp, combined goldenseal/echinacea and black pepper, and in periodically evaluating new, emerging NPs for prioritization. The UW portion of the Pharmacology Core will conduct all the necessary preclinical studies for identifying potential drug interactions with hemp and the combined goldenseal/echinacea product and associated constituents. At present, the preclinical studies will largely consist of validated in vitro screening assays for known drug metabolizing enzymes; possible interactions with drug transporters will be sub-contracted to Solvo. Bench support will be provided by a qualified postdoctoral fellow in Dr. Unadkat’s lab, Dr. Sumit Bansal, and a senior staff scientist in Dr. Rettie’s lab, Dr. Matt McDonald. Dr. Unadkat will also oversee the development of PBPK models for cannabidiol (from hemp) and goldenseal/echinacea – probe drug interactions.Analytical Core Under the parent grant, the Analytical Core is charged with 1) characterizing the bioactive constituents of the priority natural products selected for the Interaction Projects, 2) isolating and supplying the bioactive extracts of selected natural products for preclinical studies on drug interaction potentials, and 3) supporting the analysis of samples generated from the clinical human subject studies under the Interaction Projects. The Analytical Core component of this UW subcontract will focus on the third charge, mainly to provide the critical analytical support for the clinical studies on standardized hemp and goldenseal/echinacea extracts in regards to their potential for modulating drug metabolizing enzymes and drug transporters. The analysis tasks will consist of development of sensitive and specific mass-spectrometry based assays for the drug and/or metabolites of the drug probes used in the enzyme or transporter screens and key constituents present in the natural product extracts (i.e., the perpetrators). All assays will be performed in our shared research resource PK Lab in the Department of Pharmaceutics. A secondary assignment for the UW component of the Analytical Core is to provide back-up support or overflow capacity in the analysis of biological samples (i.e., blood/plasma and urine) collected from human subject studies of kratom and black pepper, under the Interaction Projects. As currently proposed, these analyses are to be handled by Dr. Mary Paine's laboratory at WSU. UW PK Lab will provide back-up LC-MS/MS support on those occasions when the WSU LC-MS facility develops major instrumentation problems. The PK Lab will also handle overflow samples generated from pre-clinical studies by investigators in the Pharmacology Core (i.e, labs of Drs. Unadkat and Rettie).
Personnel
Thummel, Kenneth E., Principal Investigator, Professor, PHARMACEUTICS • Brauchla, Calder C, Other, Research Scientist/Engineer 1 (E S 6), PHARMACEUTICS • Bansal, Sumit, Other, Postdoctoral Scholar (E S UAW Postdoc), PHARMACEUTICS • McDonald, Matthew G., Other, RESEARCH SCIENTIST/ENGINEER 3, MedChem - Rettie La, MEDICINAL CHEMISTRY • Unadkat, Jashvant D, Co-Investigator, Professor, PHARMACEUTICS • Rettie, Allan E., Co-Investigator, Professor, MEDICINAL CHEMISTRY • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, Budget Contact, Grants And Contracts Manager/specialist, PHARMACEUTICS • Royall, Frederick, eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, PCEUT - A, PHARMACEUTICS
Dynamics and Interactions of Cytochrome P450 19A1.
ATKINS, WILLIAM M. , Medicinal Chemistry
Award Date: 11/05/2020
Sponsor: Virginia Commonwealth University School of Medicine Amount: $84903
Abstract
This project aims to understand the enzyme CYP19A which is responsible for steroid biosynthesis and has been established as a drug target for Breast Cancer. We aim to characterize the protein dynamics to understand how CYP1(A interacts with drugs and substrates.
Personnel
Atkins, William M., Principal Investigator, Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Screening of Investigational Compounds to Treat, Modify or Prevent Epilepsy for the NINDS Epilepsy Therapy Screening Program (ETSP).
WHITE, HAROLD STEVE , Department Of Pharmacy
Award Date: 11/02/2020
Sponsor: University of Utah Amount: $564149
Abstract
The systemic kainic acid (KA)-induced status epilepticus (SE) model in rats is an etiologically-relevant animal model of epileptogenesis. All of the clinical characteristics observed in human patients with temporal lobe epilepsy (TLE) are also observed in the rat systemic KA model of SE and TLE. Moreover, the systemic low-dose KA paradigm is ideally suited for preclinical drug screening studies to evaluate the long-term process of epileptogenesis. As a first attempt to identify novel and potentially efficacious antiepileptogenic agents, it is necessary to define whether administration of the investigational compound during the SE insult or immediately after (e.g. during the latent period) can first modify presentation and severity of spontaneous recurrent seizures, as well as attendant comorbidities, in the rat KA-SE model of epileptogenesis. The goal of the proposed studies is to determine whether administration of promising investigational anticonvulsant compounds can also modify or attenuate the presentation of spontaneous recurrent seizures days to weeks after SE, as well as modify the SE-induced behavioral deficits associated with TLE.
Personnel
White, Harold Steve, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Haliski, Melissa, Key Personnel, Research Scientist/engineer-senior, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Genentech Fellowship - Park.
VEENSTRA, DAVID , Department Of Pharmacy
Award Date: 10/26/2020
Sponsor: Genentech, Inc. Amount: $254853
Abstract
Genentech supports a Two-Year Fellowship Program in Health Economics and Outcomes Research (HEOR) through the University and its Department of Pharmacy. In this second year of the Fellowship, two fellows are being supported.
Personnel
Veenstra, David, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Park, Yeonhee Jenny, Fellow, Postdoctoral Scholar, DEPARTMENT OF PHARMACY • Marcum, Zachary, Co-Investigator, Assistant Professor without Tenure, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Genentech Fellowship - Kim.
VEENSTRA, DAVID , Department Of Pharmacy
Award Date: 10/26/2020
Sponsor: Genentech, Inc. Amount: $254853
Abstract
Genentech supports a Two-Year Fellowship Program in Health Economics and Outcomes Research (HEOR) through the University and its Department of Pharmacy. In this second year of the Fellowship, two fellows are being supported.
Personnel
Veenstra, David, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kim, Eunice, Fellow, Postdoctoral Scholar, DEPARTMENT OF PHARMACY • Marcum, Zachary, Co-Investigator, Assistant Professor without Tenure, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
High Value Targets Working Group.
Gray, Shelly L. , Department Of Pharmacy
Award Date: 10/08/2020
Sponsor: Northern California Institute for Research and Education (NCIRE) Amount: $51161
Abstract
As Co-Investigator on this project and leader of the research network’s workgroup on identifying high-priority targets for deprescribing research and implementation activities, Dr. Gray will help direct all functions of the workgroup including designing the workgroup’s research and activities plan; supervising execution of that work plan including conduct and analysis of the research findings; providing regular progress updates to network leadership; and authoring a manuscript and relevant dissemination materials that arise from the workgroup’s research and research synthesis activities.
Personnel
Gray, Shelly L., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Devine, Emily E., Key Personnel, Professor, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Administrative Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Administrative Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Population-based Interventions to Improve Behavioral Health in a Tribal Healthcare System.
THUMMEL, KENNETH E. , Pharmaceutics
Award Date: 10/06/2020
Sponsor: Southcentral Foundation Amount: $88808
Abstract
Dr. Thummel will be responsible for overseeing work by staff in the Clinical Pharmacokinetics Lab to quantify vitamin D (VitD) concentrations in plasma samples that will be collected in Specific Aim 2 (SA2) and SA3. He will also oversee genotyping of DNA samples from the same Aims, working closely with staff in the EDGE Functional Genomics lab. He will supervise Ms. Calamia and her efforts to quantify VitD metabolites. Dr. Thummel will work with Dr. Robinson and Dr. Timothy Thornton, PhD biostatistician to oversee the statistical analyses planned for SA2 and SA3 and work closely with all project investigators on the publication of research findings. He will also support Ms. Trinidad, a Research Scientist at the Department of Bioethics and Humanities. She will train Ms. Beans in qualitative research techniques, assist with analysis of data, and results dissemination; development of study management materials for Specific Aim 2, and lay dissemination materials for Specific Aims 1, 2, and 3.Dr. Kenneth Thummel, the Milo Gibaldi Endowed Professor and Chairman of the Department of Pharmaceutics in the UW School of Pharmacy and Adjunct Professor of Environmental Health Sciences in the School of Public Health, will provide scientific direction and oversight for career development and mentorship activities related to Specific Aim 1 including focused mentoring. Ms. Susan Trinidad will assist with manuscript writing and copy editing in Specific Aims 2 and 3, and will assist Dr. Hiratsuka’s SCF based team in the development of dissemination materials, and peer-review manuscripts. Additionally, Ms. Trinidad will travel to Anchorage annually to provide technical assistance in person.
Personnel
Thummel, Kenneth E., Principal Investigator, Professor, PHARMACEUTICS • Thornton, Timothy A., Key Personnel, Associate Professor, N/A • Trinidad, Susan B, Key Personnel, Research Scientist/engineer 4, BIOETHICS & HUMANITIES • Calamia, Justina C., Other, Research Scientist/engineer 2, PHARMACEUTICS • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, Budget Contact, Grants And Contracts Manager/specialist, PHARMACEUTICS • Royall, Frederick, eGC1 Preparer, Grants And Contracts Manager/specialist, PHARMACEUTICS
SA2101693 - SAA Bansal FHCRC Ramsey.
BANSAL, AASTHAA , Department Of Pharmacy
Award Date: 09/28/2020
Sponsor: Fred Hutchinson Cancer Research Center (FHCRC) Amount: $2376
Abstract
The goal of the proposed work is to provide statistical expertise on Dr. Ramsey's funded project, supporting the accomplishment of workscope for this Genentech project at FHCRC
Personnel
Bansal, Aasthaa, Principal Investigator, Research Assistant Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Camp, Alyssa L, Budget Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Impact of Chronic Seizures on Neuropsychiatric Comorbidities in AD-Associated Models.
HALISKI, MELISSA , Department Of Pharmacy
Award Date: 09/18/2020
Sponsor: National Institute of Mental Health (NIMH) Amount: $388750
Abstract
Patients with Alzheimer’s disease (AD) experience seizures, although these events are commonly non-convulsive in nature and thus potentially missed. Despite this, little is known regarding the direct long-term impact of untreated seizures on disease progression in patients with AD. This study will directly define whether chronic seizures age-dependently aggravate cognitive and neuropsychiatric comorbidities of AD.
Personnel
Haliski, Melissa, Principal Investigator, Research Assistant Professor, DEPARTMENT OF PHARMACY • Smith, Carole L., Other, RESEARCH SCIENTIST/ENGINEER 2, Neurology: Dr. Jaya, NEUROLOGY • Jayadev, Suman, Other, ASSOC PROFESSOR WITHOUT TENURE, Neurology: Neuroge, NEUROLOGY • Zierath, Dannielle, Other, Research Scientist/Engineer 3 (E S 8), NEUROLOGY • Knox, Kevin, Other, Research Scientist/Engineer 1 (E S 6), DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Personalized Risk-AdaptIve Surveillance strategies in cancEr (PRAISE).
BANSAL, AASTHAA , Department Of Pharmacy
Award Date: 09/03/2020
Sponsor: National Institutes of Health (NIH) Amount: $449314
Abstract
This research addresses a significant problem in cancer survivorship care by using novel approaches and developing a practical tool to help resolve the uncertainty that clinicians and patients face when confronted with using new and evolving biomarker technologies to monitor for recurrence after patients have survived their primary cancer. Our holistic approach of applying the decision-making framework to three wide ranging cancer applications will inform both clinical decision-making in these areas and also future policy decisions on research investments with a transparent link between the needs for additional biomarker development and improving population outcomes.
Personnel
Bansal, Aasthaa, Principal Investigator, Research Assistant Professor, DEPARTMENT OF PHARMACY • Basu, Anirban, Co-Investigator, Professor, DEPARTMENT OF PHARMACY • Veenstra, David, Co-Investigator, Professor, DEPARTMENT OF PHARMACY • Heagerty, Patrick J., Co-Investigator, Professor, N/A • Shankaran, Veena, Co-Investigator, Assoc Professor Without Tenure, DEPARTMENT OF MEDICINE • Inoue, Lurdes, Co-Investigator, Professor, N/A • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Camp, Alyssa L, Budget Contact, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY
Effects of Informal Care for persons with Alzheimer's Disease and related dementias.
Basu, Anirban , Department Of Pharmacy
Award Date: 09/03/2020
Sponsor: University of Pennsylvania Amount: $52298
Abstract
Dr Basu’s work has focused on estimating individual treatment effects. He will work with Dr. Coe and her research team to applying these methods in a new, very policy relevant domain of the interaction between formal and informal care among the elderly.
Personnel
Basu, Anirban, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY • Luetjen, Karen H., eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Customizing Value-based Methods to Prioritize Implementation of Pharmacogenomic Clinical Decision Support For Learning Health Systems.
Devine, Emily E. , Department Of Pharmacy
Award Date: 09/02/2020
Sponsor: Agency for Healthcare Research and Quality (AHRQ) Amount: $156575
Abstract
Pharmacogenomics (PGx) – guiding drug therapy based on individuals’ genetic make-up - offers significant potential to improve drug outcomes, as 97% of the US population carries at least one potentially actionable variant. Providing PGx test results using clinical decision support (PGx-CDS) alerts embedded in health records may be a useful way to guide drug therapy. Yet, Learning Health Systems (LHSs) resist adoption because they are unsure of the value of investing in CDS systems for PGx. Determining the value of providing population-specific PGx-CDS alerts would enable LHSs to invest in those alerts that have the greatest potential for improving health care quality and outcomes in their specific populations. The objective of this proposal is to help LHSs make informed decisions about the implementation of PGx-CDS alerts specific to their populations that consider trade-offs between the cost of implementation and the potential clinical benefits to patients. Using decision modeling, in Aim 1 we will create a framework for estimating the value of PGx-CDS alerts. In Aim 2, we will adapt this framework to an online platform, creating a publically available, web-based tool that will enable customized estimates of the value of PGx-CDS alerts specific to each LHS. We will pilot and improve the tool by collaborating with stakeholder-colleagues in LHSs.Our work is responsive to the priorities outlined in AHRQ PA-17-246 in that it: 1) provides an innovative, evidence-based HIT solution to manage population health and improve quality and outcomes within LHSs in a way that makes the solution configurable across disparate LHSs, and 2) provides a platform to share and analyze practice data in a way that makes knowledge learned actionable and sharable, including tailoring messages to decision-makers. Our project is aligned with the priorities of AHRQ in that it will make healthcare safer and costs transparent, while simultaneously creating efficiencies.
Personnel
Devine, Emily E., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Veenstra, David, Key Personnel, Professor, DEPARTMENT OF PHARMACY • JIANG, SHANGQING, Other, Graduate Fellow Stipend w/ Benefits, DEPARTMENT OF PHARMACY • Mathias, Patrick C, Co-Investigator, Adjunct Assistant Professor, LAB MEDICINE • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Carlson ICER 2020-21.
CARLSON, JOSHUA J. , Department Of Pharmacy
Award Date: 08/03/2020
Sponsor: Institute for Clinical and Economic Review Amount: $667000
Abstract
Project activities will include scoping, developing a cost-effectiveness model, budget impact model and technical monograph.
Personnel
Carlson, Joshua J., Principal Investigator, Associate Professor, DEPARTMENT OF PHARMACY • Veenstra, David, Key Personnel, Professor, DEPARTMENT OF PHARMACY • Hansen, Ryan, Key Personnel, Assistant Professor, DEPARTMENT OF PHARMACY • Bloudek, Lisa, Key Personnel, Research Scientist IV, DEPARTMENT OF PHARMACY • Guzauskas, Greg, Other, Project Appointment - Overtime Exempt, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Contribution of altered lipid metabolism to resistance to cell envelope-targeting antimicrobials in MRSA.
Werth, Brian , Department Of Pharmacy
Award Date: 07/30/2020
Sponsor: National Institutes of Health (NIH) Amount: $463818
Abstract
TBA
Personnel
Werth, Brian, Principal Investigator, Assistant Professor, DEPARTMENT OF PHARMACY • Tomita, Hideaki, Key Personnel, Senior Fellow, MEDICINAL CHEMISTRY • Hines, Kelly Marie, Key Personnel, Senior Fellow, MEDICINAL CHEMISTRY • Salipante, Stephen, Co-Investigator, Asst Professor Without Tenure, LAB MEDICINE • Xu, Libin, Co-Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Cui, Yue, Co-Investigator, Asst Professor Without Tenure, ENVIRO & OCCUP HEALTH • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Camp, Alyssa L, Budget Contact, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Luetjen, Karen H., eGC1 Preparer, Grants And Contracts Manager/specialist, DEPARTMENT OF PHARMACY
Functional Dynamics of Cytochrome P4503A4.
Atkins, William M. , Medicinal Chemistry
Award Date: 07/23/2020
Sponsor: National Institutes of Health (NIH) Amount: $468683
Abstract
Cytochrome P450s, including the isoform CYP3A4, dominate drug metabolism and are responsible for many drug-drug interactions that cause toxicity, side effects, or death. Cytochrome P450s exhibit complex kinetics and allosteric properties that make prediction of drug metabolism difficult on the basis of in vitro experiments. This proposal aims to understand the biophysical and dynamic behavior of CYPS in order to better predict drug interactions and drug clearance.
Personnel
Atkins, William M., Principal Investigator, Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Oxysterols in SLOS neurodevelopment: pathological role and therapy.
XU, LIBIN , Medicinal Chemistry
Award Date: 07/16/2020
Sponsor: National Institutes of Health (NIH) Amount: $391101
Abstract
Defects in cholesterol biosynthesis lead to disorders that affect brain development, with Smith-Lemli-Opitz syndrome (SLOS) being the most common. SLOS is caused by mutations in the gene encoding 3ß-hydroxysterol-?7-reductase (DHCR7). This results in decreased levels of cholesterol and greatly increased levels of a cholesterol precursor, 7-dehydrocholesterol (7-DHC), in tissues and fluids of SLOS patients relative to normal individuals. The SLOS phenotype manifests as multiple congenital malformations, nervous sys-tem abnormalities, and autistic behavior. In fact, over 50% of SLOS children were diagnosed with autism, which is one of the strongest correlations between autism and single gene disorders. Conventional therapy for SLOS is supplementation of cholesterol, sometimes in combination with simvastatin, but these approaches do not improve neurological defects in patients. The long-term goals of this project are to elucidate the consequences of disrupted cholesterol homeostasis during neurodevelopment and to develop therapies that can ameliorate the neurological defects. We hypothesize that 7-DHC-derived oxysterols are causative factors for neurodevelopmental defects in SLOS. In this project, we will evaluate the pathological roles of 7-DHC oxysterols in neurogenesis processes in vitro and in vivo and test therapeutic approaches that can lower the levels of these oxysterols or counteract their biological actions. The knowledge generated from this study is likely to have significant impact on other diseases that are related to abnormal cholesterol biosynthesis and autism.
Personnel
Xu, Libin, Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Gamble, Lara J., Co-Investigator, Research Associate Professor, BIOENGINEERING • Xia, Zhengui, Co-Investigator, Professor, ENVIRO & OCCUP HEALTH • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, Budget/fiscal Analyst, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, Administrator, MEDICINAL CHEMISTRY
Value-based Formulary-Essentials: Testing and Expanding on Value in Prescription Drug Benefit Design.
SULLIVAN, SEAN , Department Of Pharmacy
Award Date: 07/09/2020
Sponsor: Kaiser Permanente Washington Health Research Institute Amount: $17326
Abstract
Dr. Sullivan will provide expertise in effective engagement and dissemination of study results to payersand purchasers, and will be available to meet 1-2 times per month to discuss study progress. Mr. Kreuter will provide expertise in the use of Medical Expenditure Panel Survey databases and will prepare files originating from those databases for the project, Subawardee deliverables, milestones and schedule, including Progress Reporting.
Personnel
Sullivan, Sean, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kreuter, William I., Other, RESEARCH CONSULTANT, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Jiao SAA Hutch 2020.
DEVINE, EMILY E. , Department Of Pharmacy
Award Date: 07/09/2020
Sponsor: Fred Hutchinson Cancer Research Center (FHCRC) Amount: $7987
Abstract
Staff Assignment is planned to engage Boshen Jiao as pre-doc research associate on FHCRC projects.
Personnel
Devine, Emily E., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Jiao, Boshen, Other, Graduate Fellow Stipend w/ Benefits, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
GH-VAP Vaccine Structural Analysis .
LEE, KELLY K. , Medicinal Chemistry
Award Date: 07/08/2020
Sponsor: Bill and Melinda Gates Foundation Amount: $1499995
Abstract
This abstract should express the purpose and essence of the proposed activity in language understandable to nonspecialists. Classified information should not be included. These abstracts are relied upon heavily by those charged with explaining the University's research programs to the public and the state government. Therefore, the importance of preparing them carefully cannot be overemphasized.We propose to collaborate with GH-VAP members in order to help advance infectious disease vaccine development towards a more rational, structure-based approach. The structural analysis methods we have developed through studies of the HIV Env (as a member of the BMGF CAVD) and influenza virus’ hemagglutinin glycoproteins are broadly applicable to a wide range of systems and are particularly powerful in providing structural information without the constraints of having to crystallize a protein. This opens the door to comparing protein and epitope structure in different constructs and from a range of variants with a goal of identifying how epitope structure changes in these different situations. The methods are also capable of examining antigen with flexible features such as loops and glycosylation intact, as well as in the presence of adjuvants or other components such as carrier molecules. An understanding of immunogen structures and their modes of recognition by antibodies provides a basis for iteratively altering the immunogen’s design in order to enhance the immune response.The primary biophysical and structural analytical methods we propose to use include hydrogen/deuterium-exchange mass spectrometry (HDX-MS), X-ray radical footprinting with mass spectrometry (XF-MS), small-angle X-ray scattering (SAXS), and electron microscopy (EM). These probe protein conformation and interactions with ligands such as receptors, antibodies and therapeutics. They also enable us to assess epitope stability and whether a protein is natively folded or misfolded. The approaches are amenable to a wide range of systems and sample conditions. In addition, quantitative biochemical and biophysical characterization of samples will be carried out in order to assess their compositional purity, conformational homogeneity, nativeness, and general physical properties such as stability, mass, monodispersity. Many of these techniques such as HDX-MS are frequently used by biotech and pharmaceutical companies to validate that biologic agents are properly folded as well as to assay for aggregation, degradation, and non-native structure.The specific analyses to be performed will depend on the particular collaboration, system of interest, and biological or translational question of interest. Some examples of questions include: 1) How does epitope presentation differ in different antigen constructs such as epitope scaffolds versus complete protein subunits or complexes, 2) How does antigen structure change in the presence of adjuvants, 3) What degree of conformational heterogeneity is observed in a sample, 4) How are antigens organized, distributed, and oriented on more complex vectors such as VSV, HBsAg, liposomes, and VLPs, 5) How do specific modifications to an antigen alter its structure, epitope presentation and stability? SARS-Cov-2: Given the global crisis relating to the SARS-CoV-2/COVID19 pandemic, we will prioritize analysis of antigens under development as well as analysis of the SARS-CoV-2 interactions with neutralizing antibodies and receptors. These projects will examine antigen structure, assess compositional and conformational heterogeneity of sample preparations, measure antigen stability, determine glycan composition, and characterize the antibody and receptor binding profiles of antigens. We are starting to receive and process the first of these types of samples as of March 2020.
Personnel
Lee, Kelly K., Principal Investigator, Associate Professor, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, Key Personnel, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Guttman, Miklos, Other, Assistant Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, eGC1 Preparer, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY
Modulation of drug transport at the renal proximal tubule by uremic solutes – implications in chronic kidney disease.
YEUNG, CATHERINE , Department Of Pharmacy
Award Date: 06/29/2020
Sponsor: National Institute of General Medical Sciences (NIGMS) Amount: $290819
Abstract
Dose adjustment of renally cleared drugs in patients with chronic kidney diseases (CKD) is currently based on serum creatinine concentration, a biomarker of glomerular filtration (GFR). Despite dose reduction, adverse drug reactions remain extremely prevalent in CKD patients. Often, observed changes in drug exposure do not follow predictions based on the decline in creatinine clearance (CLcr), as exemplified by penciclovir (PEN) and tenofovir (TEN). We assert that the primary cause of suboptimal drug dosing in patients with CKD is the failure of estimated CLcr to accurately reflect the functional decline of renal tubule secretory function in CKD patients, and that drugs cleared primaily by tubular secretion (vs filtration), are subject to further compromise in clearance due to inhibition of secretion by accumulating uremic solutes.Renal tubular secretion requires coordinated uptake transport at the basolateral membrane and efflux transport at the apical membrane of the proximal tubular epithelium. In vitro studies have established that accumulating uremic solutes such as hippuric acid (HA), indoxyl sulfate (IS), p-cresol sulfate (pCS), and trimethylamine N-oxide (TMAO), inhibit uptake OAT transporters. Our preliminary data suggests that these endogenous compounds also impact apical efflux transporters. We hypothesize that 1) both uptake and efflux transport proteins in the proximal tubule are inhibited by accumulating uremic solutes (HA, IS, pCS, TMAO) in individuals with CKD, and 2) inhibition of transporters by endogenous uremic solutes constitutes the principal cause of the complex nonlinear relationship between renal drug clearance and CLcr, and leads to intracellular accumulation of potential nephrotoxins.These hypotheses will be investigated using PEN and TEN as representative tubular drug transport substrates exhibiting a greater decline of renal drug clearance in CKD than that predicted by estimated CLcr. Oseltamivir carboxylate (OST) will serve as a comparative control, whose renal clearance does follow prediction by CLcr.In order to characterize the mechanisms by which uremic solutes alter tubular transporter protein function and potentiate tubular toxicity, we will use existing transfected cell technology coupled with an innovative three-dimensional, microphysiological, primary cell culture model that will allow, for the first time, dynamic measurement of transepithelial flux and real-time monitoring intracellular accumulation of model substrates penciclovir, tenofovir, and oseltamivir carboxylate. A concurrent clinical study will evaluate the same drugs in healthy subjects and patients with stage 3 or 4 chronic kidney disease.Successful completion of this innovative research program will provide in-depth insight into mechanisms that regulate tubular clearance function in the disease milieu which will lead to fundamental paradigm change in our clinical approach to managing drug dosing in CKD based upon a combination of filtration, tubular secretion, and uremic biomarkers.
Personnel
Yeung, Catherine, Principal Investigator, Acting Assistant Professor, DEPARTMENT OF PHARMACY • Zelnick, Leila, Key Personnel, Research Assistant Professor, DEPARTMENT OF MEDICINE • Unadkat, Jashvant D, Other, Professor, PHARMACEUTICS • Prasad, Bhagwat, Other, Asst Professor Without Tenure, PHARMACEUTICS • Kelly, Edward J, Other, Assoc Professor Without Tenure, PHARMACEUTICS • Himmelfarb, Jonathan, Co-Investigator, Professor, DEPARTMENT OF MEDICINE • Luetjen, Karen H., Administrative Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Contact, Grants And Contracts Manager/specialist, DEPARTMENT OF PHARMACY
CKDu and Ochratoxin-A: risk assessment studies in a microphysiological system.
KELLY, EDWARD J , Pharmaceutics
Award Date: 06/29/2020
Sponsor: National Institutes of Health (NIH) Amount: $221538
Abstract
CKDu (CKD of unknown etiology) occurs primarily in the developing world, and is associated with living and working in agricultural communities in hot climates. The cost of treating CKDu is unattainable in low-incomecountries, where 30 days of essential medications can cost up to 18 days wages. One proposed risk factor of CKDu is chronic exposure to Ochratoxin A (OTA), a common mycotoxin found in cereal grains, beans, dried fruits, wine, coffee, and tea. OTA is a demonstrated renal carcinogen in several animal species, however hazard identification in humans has been elusive due to the lack of adequate models that include hepatic bioactivation as a source of the ultimate toxic moiety. We have recently developed a coupled liver>kidney microphysiologic system (MPS) that was used to identify the specific hepatic enzymes, renal transporters, and intermediate chemical metabolites associated with aristolochic acid mediated CKDu. Cultured under constant flow, primary liver and kidney cells demonstrated localized phase-I/II enzymes and transporters, a significant advance over immortalized cell lines that rapidly lose enzyme expression and transporter polarization. In addition, primary kidney proximal tubule cells exhibited robust and biomimetic secretion of biomarkers of kidney injury.For this proposal, we have developed an innovative integrated liver>kidney MPS that incorporates both a coupled and uncoupled kidney MPS on a single chip. We propose to define the dose-response relationships of ochratoxin A and heat stress-induced nephropathy, identify the transport proteins involved in renal ochratoxin A uptake and efflux, and determine the role of first pass metabolism in ochratoxin A-induced nephropathy. A better understanding of the mechanisms of OTA-induced kidney injury will support changes in risk assessment, regulatory agency policies on allowable exposure levels, and determination of genetic risk factors in high-risk populations.
Personnel
Kelly, Edward J, Principal Investigator, Associate Professor without Tenure, PHARMACEUTICS • Van Ness, Kirk Peter, Other, RESEARCH SCIENTIST/ENGINEER 2, PCEUT - KELLY LAB, PHARMACEUTICS • Yeung, Catherine, Co-Investigator, Research Assistant Professor, DEPARTMENT OF PHARMACY • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Deprey, Teresa M, Budget Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, PCEUT - A, PHARMACEUTICS
Mechanisms of Regulation of Retinoic Acid Homeostasis.
ISOHERRANEN, NINA , Pharmaceutics
Award Date: 06/24/2020
Sponsor: National Institute of General Medical Sciences (NIGMS) Amount: $84871
Abstract
Obesity is a major public health problem with 38% of American adults being obese and rates of obesity increasing dramatically worldwide. It is estimated that obesity is second only to smoking as a cause of premature preventable death. This is largely due to the comorbidities associated with obesity including metabolic syndrome, diabetes, cardiovascular disease and nonalcoholic fatty liver disease. Yet, very little progress has been made in the development of treatments to prevent obesity and its comorbidities, and the mechanistic link between obesity and development of comorbidities is not completely understood. Several studies have shown that obese rodents develop tissue vitamin A deficiency, with tissue retinoid concentrations decreasing by a stunning 75-90%, suggesting profound metabolic dysregulation. Findings in cell systems and animal models demonstrate that retinoids regulate adipocyte differentiation and glucose and lipid metabolism and, further, that decreased retinoid concentrations are associated with progressive obesity, insulin resistance and glucose intolerance. Thus, aggregate preclinical data suggest that altered vitamin A metabolism may contribute directly to obesity progression and the development of obesity-related co-morbidities. Critically, the mechanisms underlying this dysregulated vitamin A metabolism remain poorly understood, and the relevance of these preclinical findings to human obesity is unclear. A central premise of this proposal is that altered vitamin A metabolism in obesity is a result of increased inflammatory cytokines (IL-1β, IL-6 and TNFα) in metabolic tissues, which regulate the expression of the retinoid metabolizing enzymes CYP26, LRAT, ALDH1A and RDH in adipocytes and various liver cell types. We further hypothesize that this dysregulation of vitamin A metabolism occurs in human obesity as well as in animal models. We will test our hypotheses in two specific aims: 1) to identify the enzymes and the key regulatory signals that control all-trans-retinoic acid (atRA) concentrations and vitamin A metabolic flux in human liver and adipose tissue, and 2) to establish whether adipose tissue and liver vitamin A metabolomes are altered in obese humans. We will use our state-of-the-art mass spectrometry methods, innovative metabolic flux experiments and kinetic modeling in specific cell types to characterize the key enzymes that metabolize retinoids in liver and adipose tissue and determine how the activity of these enzymes is altered in obesity. To determine whether tissue retinoids are altered in human obesity, we will conduct a cross sectional clinical study comparing visceral and subcutaneous adipose tissue, liver and serum vitamin A metabolomes in obese and non-obese subjects. The proposed studies will lay the foundation for understanding the regulation of vitamin A metabolism in human liver and adipose tissue and for determing how vitamin A metabolism may become dysregulated in obesity contributing to progressive obesity and its co-morbidities in humans. The results will generate unprecedented insight into human retinoid biology and ultimately could lead to targeted therapeutic interventions designed to restore tissue retinoid signaling as a novel strategy for the treatment of obesity and its sequela.
Personnel
Isoherranen, Nina, Principal Investigator, Professor, PHARMACEUTICS • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Deprey, Teresa M, Budget Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Deprey, Teresa M, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS
Hybrid structural mass spectrometry for rapid site-specific glycan structural elucidation.
GUTTMAN, MIKLOS , Medicinal Chemistry
Award Date: 06/17/2020
Sponsor: National Institutes of Health (NIH) Amount: $426523
Abstract
A wide variety of complex sugar structures cover most of the extracellular milieu of higher level organisms. Many of the sugars regulate host-pathogen interactions and modulate the immune system. Understanding the detailed structures of the sugars that are associated with disease onset can identify ways of preventing pathogens from infecting cells and provide better ways to detect and target cancer cells. The current proposal aims to implement recent developments in gas-phase structural analysis into existing platforms for glycobiology to provide a novel analytical tool. Such a rapid technology will be necessary for enabling large scale studies to better understand regulation of the immune response, tumor progression, and characterization of the next generation of biotherapeutics.
Personnel
Guttman, Miklos, Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Mookherjee, Abhigya, Other, Senior Fellow, MEDICINAL CHEMISTRY • Harkewicz, Richard, Other, Project Appointment - Overtime Exempt, MEDICINAL CHEMISTRY • Hines, Kelly Marie, Other, Senior Fellow, MEDICINAL CHEMISTRY • Xu, Libin, Co-Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Bush, Matthew Francis, Co-Investigator, Assistant Professor, CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, Budget/fiscal Analyst, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, Administrator, MEDICINAL CHEMISTRY
Structural and dynamic traits underlying phenotypic variation in HIV-1 Env.
LEE, KELLY K. , Medicinal Chemistry
Award Date: 06/16/2020
Sponsor: National Institutes of Health (NIH) Amount: $531081
Abstract
The envelope glycoprotein (Env) is the sole virally encoded antigen on the exterior of HIV-1 and hence is the target for neutralizing antibodies. In this unque role, it also dictates how the virus interacts with CD4 receptor and chemokine coreceptors, as well as host lectins on the surface of antigen presenting cells, serum proteins found in the blood, and antimicrobial peptides such as defensins in the mucosal mileu. Despite recent advances in mapping its architecture, we fundamentally lack an understanding of Env structural variation among diverse isolates. This variation is a defining trait of HIV that makes it a profound challenge for targeting by the immune system and for vaccine development. To overcome these barriers, it will be essential to understand Env structure and the structure and stability of neutralizing antibody epitopes on Env under physiological conditions, and to characterize how these vary across the diverse spectrum of Envs expressed in viral isolates. The primary goals of the proposed studies are to apply powerful structural analysis approaches to characterize Env structural diversity, to determine the consequences of structural variation on antibody binding, receptor reactivity, and interaction of Env with antigen presenting proteins such as lectins.
Personnel
Lee, Kelly K., Principal Investigator, Associate Professor, MEDICINAL CHEMISTRY • Williams, James A., Fellow, Predoctoral Research Associate 2, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Drug Action, Metabolism and Kinetics Training Grant.
ATKINS, WILLIAM M. , Medicinal Chemistry
Award Date: 06/15/2020
Sponsor: National Institute of General Medical Sciences (NIGMS) Amount: $503095
Abstract
The primary objective of this Pharmacological Sciences Training Grant is to develop scientists, equipped with the necessary background in the biological and chemical sciences, and training in the application of modern tools of research and instrumental techniques, to undertake and direct fundamental research related to drug action, metabolism and kinetics.Trainees follow tracks that emphasize training in four broadly defined areas; (I) drug metabolism, (II) pharmacokinetics, drug transport and delivery, (III) cellular and molecular pharmacology and (IV) structure and drug design, that presently exist in the departments of Medicinal Chemistry, Pharmaceutics and Pharmacology.Didactic components involve individualized, highly multidisciplinary programs of coursework and seminars that center around the biological and chemical sciences. Research components of the program emphasize training in mechanistic and bioanalytical aspects of drug metabolism and toxicology, pharmacokinetics and pharmacodynamics, drug transporter function and regulation, pharmacogenetics, mechanisms and regulation of cell signaling, neuropharmacology and X-ray, NMR and proteomic approaches to structure elucidation of protein-ligand interactions of pharmacological interest.
Personnel
Atkins, William M., Principal Investigator, Professor, MEDICINAL CHEMISTRY • Bajjalieh, Sandra M., Mentor, Professor, PHARMACOLOGY • Catterall, William A, Mentor, Chair, PHARMACOLOGY • Chavkin, Charles, Mentor, Professor, PHARMACOLOGY • Cirulli, VINCENZINO, Mentor, Adjunct Associate Professor, PHARMACOLOGY • Cook, David G., Mentor, Adjunct Research Assoc Prof, PHARMACOLOGY • Gardner, Richard G., Mentor, Associate Professor, PHARMACOLOGY • Hague, Chris, Mentor, Associate Professor, PHARMACOLOGY • Ho, Rodney J.Y., Mentor, Professor, PHARMACEUTICS • Hol, Wilhelmus G.J., Mentor, Adjunct Professor, PHARMACOLOGY • Hu, Shiu-Lok, Mentor, Professor, PHARMACEUTICS • Isoherranen, Nina, Mentor, Associate Professor, PHARMACEUTICS • Kalume, Franck, Mentor, Adjunct Assistant Professor, PHARMACOLOGY • Kelly, Edward J, Mentor, Assoc Professor Without Tenure, PHARMACEUTICS • Klatt, Nichole, Mentor, Asst Professor Without Tenure, PHARMACEUTICS • Kunze, Kent, Mentor, Acting Chair, MEDICINAL CHEMISTRY • Lee, Kelly K., Mentor, Assistant Professor, MEDICINAL CHEMISTRY • Lin, Yvonne S., Mentor, Asst Professor Without Tenure, PHARMACEUTICS • Mao, Qingcheng, Mentor, Associate Professor, PHARMACEUTICS • Mc Knight, G Stanley, Mentor, Professor, PHARMACOLOGY • Moon, Randall T, Mentor, Professor, PHARMACOLOGY • Nath, Abhinav, Mentor, Assistant Professor, MEDICINAL CHEMISTRY • Nathanson, Neil, Mentor, Professor, PHARMACOLOGY • Ong, Shao-En, Mentor, Assistant Professor, PHARMACOLOGY • Phillips, Paul, Mentor, Associate Professor, PHARMACOLOGY • Scott, John D, Mentor, Professor, PHARMACOLOGY • Shen, Danny D, Mentor, Professor, PHARMACEUTICS • Stella, Nephi, Mentor, Professor, PHARMACOLOGY • Storm, Daniel R, Mentor, Professor, PHARMACOLOGY • Thummel, Kenneth E., Mentor, Professor, PHARMACEUTICS • Totah, Rheem A., Mentor, Associate Professor, MEDICINAL CHEMISTRY • Unadkat, Jashvant D, Mentor, Professor, PHARMACEUTICS • Wang, Edith H., Mentor, Associate Professor, PHARMACOLOGY • Wang, Joanne, Mentor, Professor, PHARMACEUTICS • Zheng, Ning, Mentor, Professor, PHARMACOLOGY • Zweifel, Larry, Mentor, Assistant Professor, PHARMACOLOGY • Rettie, Allan E., Mentor, Professor, MEDICINAL CHEMISTRY • Prasad, Bhagwat, Mentor, Asst Professor Without Tenure, PHARMACEUTICS • Xu, Libin, Mentor, Assistant Professor, MEDICINAL CHEMISTRY • Guttman, Miklos, Mentor, Assistant Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, Budget/fiscal Analyst, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Community Pharmacist Epilepsy Services Program.
Bacci, Jennifer Lynn , Department Of Pharmacy
Award Date: 06/08/2020
Sponsor: UCB Pharma, Inc. Amount: $18660
Abstract
This project seeks to develop and evaluate a community pharmacy-based population health intervention for people living with epilepsy.
Personnel
Bacci, Jennifer Lynn, Principal Investigator, Assistant Professor, DEPARTMENT OF PHARMACY • White, Harold Steve, Key Personnel, Professor, DEPARTMENT OF PHARMACY • Stergachis, Andreas S, Key Personnel, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Camp, Alyssa L, Budget Contact, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Ahmed, Saveena, eGC1 Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY
Antihypertensives and the Aging Brain.
Marcum, Zachary , Department Of Pharmacy
Award Date: 06/05/2020
Sponsor: National Institutes of Health (NIH) Amount: $230327
Abstract
The proposed research aims to study the association between long-term antihypertensive use and brainhealth, including Alzheimer’s disease and other dementias. Successful completion of the proposed researchcould help guide the treatment of hypertension, which affects millions of Americans, in order to maximize brainhealth.
Personnel
Marcum, Zachary, Principal Investigator, Asst Professor Without Tenure, DEPARTMENT OF PHARMACY • Crane, Paul K, Mentor, Professor without Tenure, DEPARTMENT OF MEDICINE • Keene, Christopher D, Mentor, Nancy And Buster Alvord Endowed Chair In Neuropath, PATHOLOGY • Gray, Shelly L., Mentor, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Kimura, Maya, Budget Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Luetjen, Karen H., eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY
The plasma membrane monoamine transporter (PMAT): expression and role in mIBG disposition in neuroblastoma.
WANG, JOANNE , Pharmaceutics
Award Date: 05/29/2020
Sponsor: National Institutes of Health (NIH) Amount: $367715
Abstract
The long term goal of this project is to understand the physiological function of plasma membrane monoamine transporter (PMAT) and its roles in the disposition and action of xenobiotics. Previous work established PMAT as a monoamine and a polyspecific organic cation transporter expressed on the cell plasma membrane in normal tissues. While the physiological function of PMAT and its role in organic cation disposition have been characterized, little is known regarding its expression and function in diseased tissues. Recently, we and others found that PMAT is highly expressed in human neuroblastoma (NB) tissues and cell lines. Our preliminary data suggest that PMAT is aberrantly localized in intracellular organelles in human NB cells, in contrast to its normal cell surface expression. The aberrant intracellular localization of PMAT in NB cells is associated with the presence and increased expression of an alternatively spliced variant. Furthermore, we found that meta-iodobenzylguanidine (mIBG), a radiopharmaceutical used in both diagnosis and treatment of NB, is avidly transported by PMAT. Cellular uptake and retention of 131I-mIBG in tumor cells is crucial for its anti-tumor activity. Based on these data, we hypothesized that PMAT is a novel, previously unrecognized transporter involved in intracellular disposition and therapeutic efficacy of 131I-mIBG in NB. This competing renewal application focuses on understanding the expression and cellular localization of PMAT in NB and its role in systemic disposition and tumor retention of mIBG. Three specific aims are proposed. In Aim 1, we will first determine the expression and cellular localization of PMAT in NB tissues and cells by mRNA analysis, protein quantification, and immuno-colocalization studies. The functional significance of PMAT in cellular mIBG disposition will be evaluated using cultured human NB cells with stable silencing of the PMAT gene. In Aim 2, we will determine the role of the alternatively spliced variant in regulating membrane trafficking and intracellular retention of PMAT by co-transfection and co-immunoprecipitation studies. In Aim 3, we will determine the in vivo significance of PMAT in mIBG systemic disposition, tumor retention and response using a Pmat knockout model and a murine xenograft model. The proposed studies will uncover a novel molecular mechanism underlying mIBG intracellular uptake and retention in its target cells. As 131I-mIBG therapy is currently being investigated as a frontline treatment for NB, the proposed studies will pave the way for future clinical evaluation of PMAT as a prognostic factor in tumor disposition and response to 131I-mIBG therapy.
Personnel
Wang, Joanne, Principal Investigator, Professor, PHARMACEUTICS • Zhang, Yuchen, Other, Senior Fellow, PHARMACEUTICS • Hu, Tao, Other, Senior Fellow, PHARMACEUTICS • Prasad, Bhagwat, Co-Investigator, Asst Professor Without Tenure, PHARMACEUTICS • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, Budget Contact, Grants And Contracts Manager/specialist, PHARMACEUTICS • Royall, Frederick, eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, PCEUT - A, PHARMACEUTICS
Genentech Fellowship - Fox.
VEENSTRA, DAVID , Department Of Pharmacy
Award Date: 05/27/2020
Sponsor: Genentech, Inc. Amount: $227776
Abstract
Genentech supports a Two-Year Fellowship Program in Health Economics and Outcomes Research (HEOR) through the University and its Department of Pharmacy. In this second year of the Fellowship, two fellows are being supported.
Personnel
Veenstra, David, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Ahmed, Saveena, eGC1 Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Genentech Fellowship - Hong.
VEENSTRA, DAVID , Department Of Pharmacy
Award Date: 05/27/2020
Sponsor: Genentech, Inc. Amount: $227776
Abstract
Genentech supports a Two-Year Fellowship Program in Health Economics and Outcomes Research (HEOR) through the University and its Department of Pharmacy. In 2019, Genentech is expanding the Fellowship to two students.
Personnel
Veenstra, David, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Sudden cardiac arrest and circulating hydrogen sulfide.
TOTAH, RHEEM A , Medicinal Chemistry
Award Date: 05/26/2020
Sponsor: National Institutes of Health (NIH) Amount: $714436
Abstract
Sudden cardiac arrest (SCA) is a major public health concern, accounting for up to 400,000 deaths in the US alone. Despite recent progress in treatment and prevention of coronary artery disease, SCA continues to be one of the leading causes of mortality. With the exception of the implantable cardioverter-defibrillator (ICD), there are few effective approaches to SCA prevention and even fewer clues to identify individuals predisposed to underlying life-threatening arrhythmias.H2S is an important cardiac signaling gasotransmitter responsible for the protection of cardiac cells during ischemia reperfusion injury and preventing arrhythmias. Therefor any reduction in H2S levels in cardiac tissue can be toxic. This research will identify if there is an association between SCA and H2S levels in plasma or red blood cells. The protective mechanism of H2S in the heart will also be examined and factors that regulate cardiac H2S will be revealed. Once completed, this research will help uncover factors that lead to SCA and discover potential new drug targets that will make prediction and prevention much easier.
Personnel
Totah, Rheem A., Principal Investigator, Associate Professor, MEDICINAL CHEMISTRY • Gharib, Sina A., Co-Investigator, Associate Professor without Tenure, DEPARTMENT OF MEDICINE • McKnight, Barbara, Co-Investigator, Professor, BIOSTATISTICS • Lemaitre, Rozenn N., Co-Investigator, Research Associate Professor, DEPARTMENT OF MEDICINE • Sotoodehnia, Nona, Multiple PI, Associate Professor without Tenure, DEPARTMENT OF MEDICINE • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Allergan Fellowship Program in Pharmacoeconomics (Cai).
DEVINE, EMILY E. , Department Of Pharmacy
Award Date: 05/14/2020
Sponsor: Allergan, Inc. Amount: $225466
Abstract
Graduate Fellowship In Pharmacoeconomics in Health Systems/Managed Care Master of Science (M.S.) In Pharmaceutical SciencesArea of emphasis: Pharmaceutical Economics and Outcomes Research
Personnel
Devine, Emily E., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Allergan Fellowship Program in Pharmacoeconomics (Park).
DEVINE, EMILY E. , Department Of Pharmacy
Award Date: 05/14/2020
Sponsor: Allergan, Inc. Amount: $225466
Abstract
Graduate Fellowship In Pharmacoeconomics in Health Systems/Managed Care Master of Science (M.S.) In Pharmaceutical SciencesArea of emphasis: Pharmaceutical Economics and Outcomes Research
Personnel
Devine, Emily E., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Camp, Alyssa L, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 9), DEPARTMENT OF PHARMACY
Cost Effectiveness Analysis of Stem Cell Transplant in Older MDS Patients.
BANSAL, AASTHAA , Department Of Pharmacy
Award Date: 05/13/2020
Sponsor: Fred Hutchinson Cancer Research Center (FHCRC) Amount: $24264
Abstract
Dr. Bansal will serve as consortium principal investigator on Dr. Ramsey’s Ancillary cost effectiveness analysis study.
Personnel
Bansal, Aasthaa, Principal Investigator, Research Assistant Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Contact, Grants And Contracts Manager/specialist, DEPARTMENT OF PHARMACY • Ahmed, Saveena, eGC1 Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY
Can protein-mediated uptake explain lack of accurate IVIVE of transporter-mediated hepatic clearance of drugs? .
UNADKAT, JASHVANT D , Pharmaceutics
Award Date: 04/21/2020
Sponsor: Certara UK Limited Amount: $110677.35
Abstract
Successful in vitro to in vivo extrapolation (IVIVE) of transporter-mediated hepatic clearance (CLh) of drugs will expedite drug development. However, this goal remains elusive as IVIVE of CLh using human hepatocytes, considerably underpredicts the observed in vivo CLh[1,2]. While we have reported successful IVIVE of CLh,uptake of 11C-rosuvastatin (RSV) in the rat (as measured by PET imaging) using the relative expression factor (REF) and transfected cell lines, the same approach considerably underpredicted the in vivo observed CLh,uptake of 11C -RSV in humans (unpublished data). Interestingly, human hepatocytes underpredicted the in vivo 11C -RSV CLh,uptake to even a greater extent. However, using REF, transfected cell lines (OATP1B1/1B3/2B1 and NTCP) accurately predicted RSV CLh,uptake in human hepatocytes. Thus, the estimation of RSV CLh,uptake using transfected cell lines/hepatocytes is missing some endogenous factor present in vivo. One possibility is plasma proteins and/or soluble endogenous factor(s) in plasma. In human hepatocytes, RSV is taken up by OATPs as well as NTCP. Since OATPs are allosteric, it is very possible that an endogenous factor in plasma may increase the efficiency of RSV transport in vivo. Indeed, RSV CLh,uptake (both active transporter-mediated uptake and passive diffusion) in hepatocytes (and those of other statins) has been shown to be enhanced by albumin or plasma[3]. These observations raise the following important questions: 1) What are the constituents if any in plasma (other than albumin) that enhance CLh,uptake of drugs? 2) For successful IVIVE should all transport studies with hepatocytes/transfected cells be conducted in the presence of albumin, plasma or plasma water? 3) Is the protein-mediated increase in CLh,uptake present only when the drug is highly bound? 4) Should drug uptake studies be conducted in the presence of plasma (or proteins) for all important uptake transporters (e.g. OCT1, OAT2, NTCP, OATPs). In other words, is the protein-mediated effect selective for only OATPs? Our preliminary data suggests that NTCP is not affected. 5) Why is the passive diffusion of RSV (and other statins) increased by plasma as reported by Benet et al.[3]? Though some hypotheses for this protein-mediated effect have been proposed by Sugiyama and Benet, none of them can explain all the observed phenomena. This proposal will address all the above questions and will result in recommendation of best practices when conducting uptake studies to allow accurate IVIVE of CLh,uptake of drugs. The drugs tested will span a wide variety of therapeutics categories (e.g. statins, antidiabetics) and transporters (e.g. OATPs, OCT2, OAT2, NTCP). Such studies are critical to streamline and efficiently conduct studies for IVIVE during drug development. Including plasma or plasma protein(s) in transport experiments is not only costly but also poses technical challenges such as LC-MS/MS quantification of cellular uptake due to extensive plasma protein binding. Thus, identifying when to, and when not to include plasma or plasma proteins in uptake studies (transfected cells or hepatocytes), is critical to maximize efficiency and minimize cost/technical challenges for IVIVE of CLh of drugs.
Personnel
Unadkat, Jashvant D, Principal Investigator, Milo Gibaldi Endowed Professorship In Pharmaceutic, PHARMACEUTICS • YIN, MENGYUE, Key Personnel, Research Assistant (E S UAW ASE), PHARMACEUTICS • Eng, Matthew N., Administrative Contact, ADMINISTRATOR, Department of Pharmaceutics, PHARMACEUTICS • Deprey, Teresa M, Budget Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Deprey, Teresa M, eGC1 Preparer, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS
Pharmacology of Drugs of Abuse During Pregnancy.
Unadkat, Jashvant D , Pharmaceutics
Award Date: 04/16/2020
Sponsor: National Institute on Drug Abuse (NIDA) Amount: $47585
Abstract
Use of marijuana amongst pregnant women in the US is increasing. A major concern of marijuana use by pregnant women is the transfer of cannabinoids across the placental barrier, leading to placental (and therefore fetal) toxicity. Studies proposed in this P01 will elucidate how and to what extent the maternal-placental-fetal exposure to cannabinoids is altered during pregnancy and how to predict these changes. Completion of these studies will significantly advance our ability to predict the risks of using marijuana during pregnancy and have the potential to reveal strategies to minimize such risks. This P01 addresses a significant public health problem that cannot be addressed using the traditional approach of conducting a clinical trial.
Personnel
Unadkat, Jashvant D, Principal Investigator, Professor, PHARMACEUTICS • Sachar, Madhav, Fellow, Senior Fellow, PHARMACEUTICS • Czuba, Lindsay, Fellow, Senior Fellow, PHARMACEUTICS • Yabut, King, Other, Research Assistant (E S UAW ASE), PHARMACEUTICS • Chamonica Hernandez, Marle, Other, Research Study Assistant (NE S SEIU 925 Non Supv), OBGYN/ADMIN • Billington, Sarah, Other, Senior Fellow, PHARMACEUTICS • Patilea-Vrana, Gabriela, Other, PREDOCTORAL RESEARCH ASSOCIATE 2, PCEUT - UNADKAT, PHARMACEUTICS • Taylor, Susan Margaret, Other, COUNSELING SERVICES COORDINATOR, OPPE Staff, PHARMACY-DEAN'S OFFICE • Macdonald, James, Other, RESEARCH SCIENTIST/ENGINEER 3, Enviro & Occup Heal, ENVIRO & OCCUP HEALTH • Shaikh, Abdul Basit A H, Other, Senior Fellow, PHARMACEUTICS • Han, Lyrialle W, Other, Research Assistant (E S UAW ASE), PHARMACEUTICS • Nielsen, Iris, Other, LIMITED TERM APPOINTMENT - PROF STAFF, Department, DEPARTMENT OF MEDICINE • Amory, John K., Co-Investigator, Professor, DEPARTMENT OF MEDICINE • Prasad, Bhagwat, Co-Investigator, Assistant Professor without Tenure, PHARMACEUTICS Kelly, Edward J, Co-Investigator, Associate Professor without Tenure, PHARMACEUTICS • Isoherranen, Nina, Co-Investigator, Professor, PHARMACEUTICS • Mao, Qingcheng, Co-Investigator, Associate Professor, PHARMACEUTICS • Benson, Lyndsey S, Co-Investigator, Acting Assistant Professor, OBGYN/ADMIN • Bammler, Theodor K., Co-Investigator, RESEARCH SCIENTIST/ENGINEER-SENIOR, Enviro & Occup, ENVIRO & OCCUP HEALTH • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, Budget Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, PCEUT - A, PHARMACEUTICS
NextGen Targeted and Long-acting Combination ART for Children with HIV.
HO, RODNEY J.Y. , Pharmaceutics
Award Date: 04/16/2020
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) Amount: $1026862
Abstract
The Targeted, Long-acting and Combination Anti-Retroviral Therapeutic (TLC-ART) Program has developed a scalable, drug-combination nano-platform technology called DcNP that enables the stabilizing of insoluble and soluble antiretroviral drugs together in an injectable suspension.The proposed plan will test this hypothesis with a set of milestone-driven aims based on a defined target product profile (TPP). These aims will be guided by an external advisory board (EAB) through scheduled and on-demand meetings. The integrated, first research focus objectives are intended to progress to preclinical development with three additional objectives for a lead and a backup DCNP selected for progression to R33 development with NHP efficacy study.
Personnel
Ho, Rodney J.Y., Principal Investigator, Professor, PHARMACEUTICS • Kinman, Loren M., Other, RESEARCH SCIENTIST/ENGINEER 3, PCEUT - HO LAB, PHARMACEUTICS • Perazzolo, Simone, Other, Senior Fellow, PHARMACEUTICS • Coronado, Ernesto, Other, Research Scientist/Engineer 2 (E S 7), PHARMACEUTICS • Jonsson, Christine Anne, Other, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE • Beima-Sofie, Kristin M, Co-Investigator, Acting Assistant Professor, GLOBAL HEALTH • Collier, Ann C, Co-Investigator, Professor without Tenure, DEPARTMENT OF MEDICINE • Shen, Danny D, Co-Investigator, Professor Emeritus, PHARMACEUTICS • McConnachie, Lisa, Co-Investigator, RESEARCH SCIENTIST/ENGINEER 4, PCEUT - HO LAB, PHARMACEUTICS • Koehn, Josefin, Co-Investigator, RESEARCH SCIENTIST/ENGINEER 3, PCEUT - HO LAB, PHARMACEUTICS • Jonsson, Christine Anne, Administrative Contact, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE • Jonsson, Christine Anne, Budget Contact, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE • Jonsson, Christine Anne, eGC1 Preparer, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE
Structure, dynamics and variation in influenza hemagglutinin-driven fusion.
LEE, KELLY K. , Medicinal Chemistry
Award Date: 04/14/2020
Sponsor: National Institutes of Health (NIH) Amount: $396951
Abstract
The influenza hemagglutinin fusion glycoprotein (HA) performs the essential function of targeting host cells for infection and mediating entry and delivery of the viral genome. Here we propose to apply innovative structural, biophysical and deep sequencing approaches to probe structural and functional variation among diverse influenza HA glycoproteins and variants of influenza virus that exhibit different overall morphologies. A more complete understanding of HA-mediated membrane fusion and the extent to which this process is conserved among diverse influenza virus strains can provide valuable new information to improve the design and targeting of antiviral agents and may be valuable for selection of vaccine immunogens.
Personnel
Lee, Kelly K., Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Hom, Nancy, Other, Senior Fellow, MEDICINAL CHEMISTRY • Williams, James A., Other, Research Assistant (E S UAW ASE), MEDICINAL CHEMISTRY • Mangala Prasad, Vidya, Other, Senior Fellow, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, Fda Seiu - Project, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Role of epithelial cell intrinsic vitamin A metabolism in regulating immune homeostasis in the gut.
ISOHERRANEN, NINA , Pharmaceutics
Award Date: 04/07/2020
Sponsor: Brown University Amount: $39262
Abstract
For the studies proposed in this application, throughout the funding period we will conduct all the labeled and unlabeled retinoic acid, retinol, retinyl ester and RBP4 measurements in the biological samples collected using our validated and sensitive liquid chromatography mass spectrometry methods, to aid in determining the role of the microbiome in regulating retinoid metabolism and vitamin A homeostasis and in understanding the role of Rdh7 in retinoid biosynthesis. We will be responsible for all sample preparation and LC-MS/MS analysis. We will also prepare the quantitative reports of the results generated from the above studies to facilitate publication of the results and aid in interpretation of the biochemistry of retinoid metabolism.
Personnel
Isoherranen, Nina, Principal Investigator, Associate Professor, PHARMACEUTICS • Kirkwood, Jay, Other, Research Scientist/engineer 2, PHARMACEUTICS • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, Budget Contact, Grants And Contracts Manager/specialist, PHARMACEUTICS • Royall, Frederick, eGC1 Preparer, Grants And Contracts Manager/specialist, PHARMACEUTICS
Functional Dynamics of P-glycoprotein.
ATKINS, WILLIAM M. , Medicinal Chemistry
Award Date: 03/30/2020
Sponsor: National Institutes of Health (NIH) Amount: $299338
Abstract
This project aims to understand the mechanism of a protein, P-glycoprotein, that contributes to cancer cell drug resistance and the clearance and pharmacokinetics of most drugs. The mechanism by which P-glycoprotein (P-gp) recognizes and exports such a wide range of drugs is not known. P-gp utilizes the hydrolysis of ATP for the energy required to pump drugs out of cells but the coupling between ATP hydrolysis and drug export is not known. The major hypothesis of this proposal is that different drugs elicit different conformations of P-gp that differentially favor ATP hydrolysis. With a better understanding of P-gp mechanism, it will be possible to design P-gp inhibitors to improve the efficacy of anticancer drugs or to improve the pharmacokinetics of other drugs.
Personnel
Atkins, William M., Principal Investigator, Professor, MEDICINAL CHEMISTRY • Dabrowski, Michael J., Other, Research Scientist/engineer 2, MEDICINAL CHEMISTRY • Li, Jiarong Mavis, Other, Predoctoral Research Associate 2, MEDICINAL CHEMISTRY • Nath, Abhinav, Co-Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Beat MS.
CARLSON, JOSHUA J. , Department Of Pharmacy
Award Date: 03/27/2020
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) Amount: $53206
Abstract
Dr. Carlson, will perform an economic analysis alongside of the clinical trial, BEAT-MS. Specifically, he will be responsible for the study design, data analysis, and interpretation of data for the within trial economic analyses and the development, analysis and interpretation of the simulation model for the long-term economic analysis. He will participate the development of the protocol, study materials, and data collection forms related to the CEA. He will advise on all project aims from the health economics perspective.
Personnel
Carlson, Joshua J., Principal Investigator, Associate Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, Budget Contact, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY • Luetjen, Karen H., eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Characterizing the broad antibody response to HIV superinfection.
LEE, KELLY K. , Medicinal Chemistry
Award Date: 03/25/2020
Sponsor: National Institutes of Health (NIH) Amount: $109371
Abstract
A collaborative effort between the UW Lee lab and Fred Hutchinson Cancer Research Center lab’s led by Dr. Julie Overbaugh and colleagues, Drs. Jesse Bloom and Frederick Matsen will apply state-of-the-art structural, biophysical, and evolutionary analytical methods to understand the development of virus neutralization breadth in the context of HIV superinfection.
Personnel
Lee, Kelly K., Principal Investigator, Associate Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Effects of Retinoids on CYP2D6 Activity and Variability in Special Populations.
HEBERT, MARY F , Department Of Pharmacy
Award Date: 03/24/2020
Sponsor: National Institutes of Health (NIH) Amount: $549949
Abstract
CYP2D6, a key drug-metabolizing enzyme, is involved in the metabolism of ~20% of all drugs. We hypothesize that natural variation in retinoic acid concentrations and retinoid signaling in the liver regulate CYP2D6 expression and activity in humans, which in turn contributes to CYP2D6 pharmacokinetic variability and CYP2D6 induction during pregnancy. We will take a mechanistic approach and test the relationship between retinoid concentrations and CYP2D6 activity in 2 studies evaluating from the perspective of CYP2D6 induction during pregnancy, repression of induction with vitamin A administration and repression of normal CYP2D6 activity with 13-cis-retinoic acid (isotretinoin) in non-pregnant adolescent patients. Pregnant and adolescent patients often require treatment for chronic conditions, which can include CYP2D6 substrates. After accounting for genetic variation, there is still a great deal of unaccounted variability in CYP2D6 activity in these special populations making clinical management challenging. Basic science studies suggest that retinoids play an important role in CYP2D6 regulation. Our objective is to understand the role of retinoids in CYP2D6 activity in pregnant, postpartum and adolescent patients and translate new laboratory findings into humans. Our Specific Aims are: Specific Aim 1. To determine if vitamin A administration decreases CYP2D6 activity during pregnancy. In this aim, we will evaluate the effect of vitamin A administration on pregnancy-induced CYP2D6 activity. This study will provide mechanistic understanding of CYP2D6 induction and variability during pregnancy as well as provide a potential clinical strategy for management of pregnant women that require CYP2D6 substrates.Specific Aim 2. To investigate if isotretinoin (13-cis-retinoic acid) administration decreases CYP2D6 activity in adolescent patients. In this aim, we will conduct a drug-drug interaction study evaluating the effects of 13-cis-retinoic acid on non-induced CYP2D6 activity in adolescent patients. Secondary analysis will evaluate the relationship between retinoid concentrations and CYP2D6 activity in these special populations. In both Specific Aims we will utilize dextromethorphan as our CYP2D6 probe substrate. Through these complementary aims, we will be the first to conduct mechanistic testing of endogenous regulation of CYP2D6 activity in humans. The results could overcome a critical barrier to safe and effective administration of CYP2D6 substrates in adolescent and pregnant patients. Based on our compelling preliminary data, we expect to identify a novel mechanism of CYP2D6 regulation in humans and a potential management strategy for CYP2D6 induction and variability during pregnancy, with the intention of improving safety and efficacy of medications for these vulnerable patients. This work is critical for the provision of individualized therapy and along with genetics, the first step in development of an endogenous biomarker for CYP2D6 activity.
Personnel
Hebert, Mary F, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Easterling, Thomas R, Key Personnel, Professor Without Tenure, OBGYN/ADMIN • Isoherranen, Nina, Key Personnel, Associate Professor, PHARMACEUTICS • Vary, James, Key Personnel, Asst Professor Without Tenure, DEPARTMENT OF MEDICINE • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Contact, Grants And Contracts Manager/specialist, DEPARTMENT OF PHARMACY • Luetjen, Karen H., eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Approaches to Improve the Efficacy of Prime-boost Immunization against HIV/AIDS.
HU, SHIU-LOK , Pharmaceutics
Award Date: 03/13/2020
Sponsor: National Institutes of Health (NIH) Amount: $891161
Abstract
To date, the only vaccine trial (RV144) that has shown any protective efficacy against HIV acquisition is based on a poxvirus prime – protein boost immunization strategy. Although the efficacy achieved was modest (~31%), these findings provide a strong rationale to seek improvements for the prime-boost immunization approach and to gain better insight on the nature of the protective immunity achieved. Correlate studies of the RV144 trial indicated that antibodies against the hypervariable loops 1 and 2 (V1/V2) region of HIV envelope protein (Env) and high levels of antibody-dependent cellular cytotoxicity (ADCC) activities inversely correlated with the risk of HIV-1 acquisition. Neutralizing antibodies (Nabs) were generated, but were primarily against sensitive (“Tier 1”) isolates, with little or no activity against the more resistant (“Tier 2”) strains typical of circulating viruses. Thus, much of the current effort in HIV vaccine research aims to elicit Tier 2 Nabs and to improve the potency and the breadth of non-neutralizing antibody responses, including V1/V2 directed antibodies and antibodies that can mediate ADCC. Using a replication-competent poxvirus for priming and gp120 for boosting, we were able to induce Nab against heterologous Tier 2 viruses as well as cross-reactive V1/V2-specific antibodies and high levels of ADCC activities in rabbits. In this application, we propose to examine novel immunogens and immunization approaches to further enhance the breadth and potency of the Nab and non-Nab responses achieved and to determine if findings in rabbits can be translated to non-human primates. We hypothesize that by presenting the Env antigen in a native trimer form with the conserved CD4 binding site unmasked, we will enhance cross-reactive Nab, and by using polyvalent Env immunogens, we will amplify responses to conserved epitopes, while broadening strain-specific responses, including those directed to variable regions. The enhanced breadth and potency of both Nab and non-Nab responses, including V1/V2-directed antibodies and those that mediate antiviral effector functions, such as ADCC, will contribute to protection against challenge in a non-human primate model. The Specific Aims are: (1) To determine if trimeric Env, instead of monomeric gp120, when used as the boosting immunogen in a prime-boost regimen may improve the breadth or potency of Nab responses; (2) To determine if the ability of a highly conserved glycan (N197) to modulate Env immunogenicity is dependent on the use of trimeric Env, instead of monomeric gp120; (3) To determine if polyvalent, rather than monovalent Env, when used in a prime-boost immunization regimen, can improve the breadth and potency of Env-specific antibody responses; and (4) To examine if immunization regimens down-selected from the preceding studies in rabbits can be translated to macaques and if the immune responses generated can protect against SHIV challenge. If successful, insights obtained from these studies will inform the clinical development of vaccines and vaccine strategies that may be more effective than those used in RV144 to prevent HIV-1 acquisition in humans.
Personnel
Hu, Shiu-Lok, Principal Investigator, Professor, PHARMACEUTICS • Firpo, Patricia S., Other, RESEARCH SCIENTIST/ENGINEER-SENIOR, Hu Lab - PRIMA, REGIONAL PRIMATE CTR • Cleveland, Bradley R., Other, RESEARCH SCIENTIST/ENGINEER 3, PCEUT - HU LAB, PHARMACEUTICS • Guo, Wenjin, Other, RESEARCH SCIENTIST/ENGINEER 3, PCEUT - HU LAB, PHARMACEUTICS • Lee, Kelly K., Co-Investigator, Associate Professor, MEDICINAL CHEMISTRY • Deprey, Teresa M, Administrative Contact, Grants And Contracts Manager/Specialist (E S 8), PHARMACEUTICS • Royall, Frederick, Budget Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, PCEUT - A, PHARMACEUTICS • Diamond, Deborah L, eGC1 Preparer, RESEARCH MANAGER, PCEUT - ADMIN, PHARMACEUTICS
Rational Integration of clinical SEquencing (RISE).
VEENSTRA, DAVID , Department Of Pharmacy
Award Date: 03/09/2020
Sponsor: National Institutes of Health (NIH) Amount: $252190
Abstract
The University of Washington subcontract will be directed by Dr. David Veenstra, who will be responsible for developing cost effectiveness models for genomic sequencing. Dr. Veenstra will have responsibility for all administrative and scientific activities conducted at University of Washington. He will oversee study personnel and will ensure completion of all study activities. Dr. Veenstra will supervise the work of the senior scientist and a graduate student research assistant.
Personnel
Veenstra, David, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Guzauskas, Greg, Other, Research Scientist/Engineer 4 (E S 9), DEPARTMENT OF PHARMACY • Spencer, Scott, Other, Research Assistant (E S UAW ASE), DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Kimura, Maya, Budget Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Ahmed, Saveena, eGC1 Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY
Characterizing the broad antibody response to HIV superinfection.
Lee, Kelly K. , Medicinal Chemistry
Award Date: 02/29/2020
Sponsor: National Institutes of Health (NIH) Amount: $50627
Abstract
A collaborative effort between the UW Lee lab and Fred Hutchinson Cancer Research Center lab’s led by Dr. Julie Overbaugh and colleagues, Drs. Jesse Bloom and Frederick Matsen will apply state-of-the-art structural, biophysical, and evolutionary analytical methods to understand the development of virus neutralization breadth in the context of HIV superinfection.
Personnel
Lee, Kelly K., Principal Investigator, Associate Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lee, Erik, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Defining the Infant Immune Response to HIV.
LEE, KELLY K. , Medicinal Chemistry
Award Date: 02/29/2020
Sponsor: National Institutes of Health (NIH) Amount: $141741
Abstract
A major hurdle to developing a protective HIV vaccine is our inability to define a pathway to generate protective neutralizing antibodies. A recent study by our group showed that infants make notably broad and potent HIV neutralizing antibody responses, and do so relatively quickly. We propose to study how they accomplish this so that this information can be used help define more promising vaccine approaches.
Personnel
Lee, Kelly K., Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Budget Contact, Administrator, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, Administrator, MEDICINAL CHEMISTRY
Repurposing Oral TLD (Tenofovir, Lamivudine, Dolutegravir) to a Long-Acting Injectable Combination HIV Medicine Using a Novel Technology.
Ho, Rodney J.Y. , Pharmaceutics
Award Date: 02/27/2020
Sponsor: UnitAid Secretariat Amount: $6962027
Abstract
The repurpose and transformative project is to take a current oral drug with 3 HIV-medicines in a combination called TLD (tenofovir, lamivudine and dolutegravir) into a long-acting dosage form that will last at least 4 weeks. Less frequent dosing that will maintain effective drug levels could improve patient adherence to drug therapy and maximize viral suppression (viral rebound is linked to premature death). This original first-line oral 3-drug combination dosing is being planned by the WHO to be widely available world-wide in late 2020. With an innovative breakthrough enabling technology that the University of Washington’s Targeted, Long-acting and Combination Anti-Retroviral Therapeutic (TLC-ART) program team has developed, we seek the support of UNITAID to transform the oral short-acting TLD HIV medicine to long-acting TLD injectable product at a value with a manufacturing process adaptive for low to middle income countries where HIV viral suppression and improve patient adherence is needed.
Personnel
Ho, Rodney J.Y., Principal Investigator, Professor, PHARMACEUTICS • Mu, Qingxin, Other, RESEARCH SCIENTIST/ENGINEER 3, PHARM:Pharmaceutics, PHARMACEUTICS • Fung, Han Wai M, Other, Research Scientist/Engineer 3 (E S 8), PHARMACEUTICS • Hartman, Matthew H, Other, Program Coordinator (NE S SEIU 925 Non Supv), PHARMACEUTICS • Coronado, Ernesto, Other, Research Scientist/Engineer 2 (E S 7), PHARMACEUTICS • Gill, Virginia B, Other, Research Scientist Engineer 1, PHARMACEUTICS • Perazzolo, Simone, Other, Postdoctoral Scholar, PHARMACEUTICS • Jonsson, Christine Anne, Other, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE • Koehn, Josefin, Other, RESEARCH SCIENTIST/ENGINEER 3, PCEUT - HO LAB, PHARMACEUTICS • Kinman, Loren M., Other, RESEARCH SCIENTIST/ENGINEER 3, PCEUT - HO LAB, PHARMACEUTICS • Collier, Ann C, Co-Investigator, Professor without Tenure, DEPARTMENT OF MEDICINE • Shen, Danny D, Co-Investigator, Professor Emeritus, PHARMACEUTICS • Jonsson, Christine Anne, Administrative Contact, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE • Jonsson, Christine Anne, Budget Contact, MANAGER OF PROGRAM OPERATIONS, Department of Medic, DEPARTMENT OF MEDICINE
Contribution of oxysterol detoxification by glutathione S-transferases to SLOS pathogenesis.
XU, LIBIN , Medicinal Chemistry
Award Date: 01/23/2020
Sponsor: Smith-Lemli-Opitz/RSH Foundation Amount: $20000
Abstract
Decreased levels of cholesterol and increased levels of its immediate precursor, 7-dehydrocholesterol (7-DHC), is the hallmark of Smith-Lemli-Opitz syndrome (SLOS). Recent findings by us and others suggest that the accumulation of 7-DHC and its oxidative metabolites, i.e., oxysterols, contributes significantly to the SLOS pathogenesis. 7-DHC was found to be extremely prone to undergo free radical oxidation, leading to a large number of oxysterols and some of these oxysterols have been found in biological samples of animal models and human patients. However, the oxysterol profiles appear to be tissue specific. Some of these oxysterols are highly electrophilic, which make them reactive to form adducts with proteins and DNA. It is known that electrophiles in the biological environment are normally detoxified by conjugation with glutathione (GSH) under the catalysis of glutathione S-transferases (GSTs). Thus, we hypothesize that the differential levels of 7-DHC-derived oxysterols, such as DHCEO, in brain and liver are caused by the different expression profiles of GSTs in these tissues. Our preliminary work found that human liver cytosol (most GSTs are in the cytosol), but not human brain cytosol, catalyzes the conjugation reaction between GSH and a major primary oxysterol. In this work, we propose to first identify the active GST isoforms that catalyze the conjugation reaction. We will then examine the level of GSH-oxysterol adduct in tissues of mouse and rat models of SLOS and in blood samples of SLOS patients. We will further evaluate the effect of antioxidant treatment on the level of GSH-oxysterol adduct in the AY9944-treated rat model. This work will assess the potential of using GSH-oxysterol adducts as readily measurable biomarkers for disease severity and for the evaluation of therapeutic interventions.
Personnel
Xu, Libin, Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Ross, Dylan Hayes, Other, Research Assistant, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY • Lidzbarski, Erik August Lee, Budget Contact, BUDGET/FISCAL ANALYST, MedChem - Admin, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, ADMINISTRATOR, Department of Medicinal Chemistry, MEDICINAL CHEMISTRY
Screening of Investigational Compounds to Treat, Modify or Prevent Epilepsy for the NINDS Epilepsy Therapy Screening Program (ETSP).
WHITE, HAROLD STEVE , Department Of Pharmacy
Award Date: 01/10/2020
Sponsor: National Institute of Neurological Disorders and Stroke (NINDS) Amount: $358221
Abstract
The systemic kainic acid (KA)-induced status epilepticus (SE) model in rats is an etiologically-relevant animal model of epileptogenesis. All of the clinical characteristics observed in human patients with temporal lobe epilepsy (TLE) are also observed in the rat systemic KA model of SE and TLE. Moreover, the systemic low-dose KA paradigm is ideally suited for preclinical drug screening studies to evaluate the long-term process of epileptogenesis. As a first attempt to identify novel and potentially efficacious antiepileptogenic agents, it is necessary to define whether administration of the investigational compound during the SE insult or immediately after (e.g. during the latent period) can first modify presentation and severity of spontaneous recurrent seizures, as well as attendant comorbidities, in the rat KA-SE model of epileptogenesis. The goal of the proposed studies is to determine whether administration of promising investigational anticonvulsant compounds can also modify or attenuate the presentation of spontaneous recurrent seizures days to weeks after SE, as well as modify the SE-induced behavioral deficits associated with TLE.
Personnel
White, Harold Steve, Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Haliski, Melissa, Key Personnel, Research Scientist/engineer-senior, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY • Luetjen, Karen H., eGC1 Preparer, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY
Defining the Infant Immune Response to HIV.
LEE, KELLY K. , Medicinal Chemistry
Award Date: 01/09/2020
Sponsor: National Institutes of Health (NIH) Amount: $46350
Abstract
A major hurdle to developing a protective HIV vaccine is our inability to define a pathway to generate protective neutralizing antibodies. A recent study by our group showed that infants make notably broad and potent HIV neutralizing antibody responses, and do so relatively quickly. We propose to study how they accomplish this so that this information can be used help define more promising vaccine approaches.
Personnel
Lee, Kelly K., Principal Investigator, Assistant Professor, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Administrative Contact, Administrator, MEDICINAL CHEMISTRY • Kanov, Jeanine M., Budget Contact, Administrator, MEDICINAL CHEMISTRY • Kanov, Jeanine M., eGC1 Preparer, Administrator, MEDICINAL CHEMISTRY
Impact of anticholinergic and dopamine receptor blocking drug exposure on Parkinson Disease trajectory and outcomes.
GRAY, SHELLY L. , Department Of Pharmacy
Award Date: 01/06/2020
Sponsor: National Institutes of Health (NIH) Amount: $31728
Abstract
As Co-Investigator on this project and leader of the research network’s workgroup on identifying high-priority targets for deprescribing research and implementation activities, Dr. Gray will help direct all functions of the workgroup including designing the workgroup’s research and activities plan; supervising execution of that work plan including conduct and analysis of the research findings; providing regular progress updates to network leadership; and authoring a manuscript and relevant dissemination materials that arise from the workgroup’s research and research synthesis activities.
Personnel
Gray, Shelly L., Principal Investigator, Professor, DEPARTMENT OF PHARMACY • Kimura, Maya, Administrative Contact, ADMINISTRATOR, Department of Pharmacy, DEPARTMENT OF PHARMACY • Luetjen, Karen H., Budget Contact, GRANTS AND CONTRACTS MANAGER/SPECIALIST, Pharm - A, DEPARTMENT OF PHARMACY • Ahmed, Saveena, eGC1 Preparer, Program Operations Analyst (E S 7), DEPARTMENT OF PHARMACY