Improving Prediction of Drug Action

改善药物作用的预测

• 批准号: 9100795
• 负责人: Joshua C. Denny
• 金额: $ 256.42万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100795
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adverse effects; Alleles; Antigens; Arrhythmia; Cardiac Myocytes; Cells; Cessation of life; Clinical Medicine; Clinical Research; Collection; Computerized Medical Record; Cross Infection; DNA; Data; Data Analyses; Development; Drug Hypersensitivity; Drug Tolerance; Drug effect disorder; Drug usage; Electronic Health Record; Event; Exposure to; Genetic; Genomics; Goals; Healthcare Systems; Hospitalization; Hypersensitivity; Immunity; Individual; Investments; Knowledge; Legal patent; Link; Long QT Syndrome; Mediating; Methodology; Methods; Minority; Modeling; Molecular; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacotherapy; Phenotype; Phosphotransferases; Play; Population; Precision Phenomics; Process; Reaction; Resources; Risk; Role; Safety; Sampling; Scanning; Science; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translations; Variant; Withdrawal; Work; abacavir; base; cohort; cost; data management; design; drug candidate; drug development; drug discovery; genomic predictors; high risk; improved; improved outcome; individual patient; mortality; new technology; non-compliance; novel therapeutics; patient population; phenome; pleiotropism; predictive modeling; prevent; public health relevance; repository; response; risk variant; success; tool

 DESCRIPTION (provided by applicant): Improving prediction of drug action Drugs are variably effective and cause adverse drug reactions (ADRs). ADRs extract major costs at individual and societal levels, leading to medication non-compliance, inefficacy, toxicity, hospitalization, and death. They can be "on-target" or "off-target", they occur across the spectrum of therapies, and they have an important, and increasing, impact not only on the way in which drugs are used in individual subjects and across healthcare systems but on the way in which new candidate molecules are developed. This Center of Excellence has as its major goal the elucidation of new mechanisms underlying variability in drug action and ADRs. We bring to this effort a unique collection of new tools and resources that enable us to confidently predict rapid development of entirely new classes of knowledge that will be a paradigm-shift from current norms of slow, incremental progress. Project 1 focuses on QT interval prolongation by drugs, a major cause for drug relabeling and withdrawals over the last two decades. Conventional wisdom has focused on the drug block of the "HERG channel" as the major mechanism, but we present compelling data that other pathways play a critical role. We will integrate the results of our previous genomic, molecular, cellular, and clinical studies in the field, exciting new data on the role of P3 kinase in this ADR, and the capability of generating cardiomyocytes from individuals whose drug response phenotypes we have established to develop new paradigms to identity risk in new drug candidates and across patient populations. Project 2 focuses on immunologically-mediated ADRs, and uses a unique resource of cells and DNA from patients with drug hypersensitivity or drug tolerance in the face of a specific HLA risk allele to define associations between HLA alleles, specific T-cell receptor usage and severe T-cell mediated drug hypersensitivity. Our goal is to test a new heterologous immunity model of drug hypersensitivity to explain this phenotypic variability and inform the development of new predictive models. Project 3 applies the new technology of phenome-wide scanning that we have pioneered to a large cohort of subjects with genomic and longitudinal electronic medical record data to broadly repurpose drugs for new indications and refine prediction of long QT-related, HLA-related, and other ADRs. The results of work in the Center will thus advance our long term goal of improving the outcome of drug therapy by reducing the burden of ADRs, improving prediction in an individual subject, repurposing available drugs, and providing new tools to the drug development process to reduce ADR risk.