Improving Prediction of Drug Action

改善药物作用的预测

• 批准号: 9194462
• 负责人: Joshua C. Denny
• 金额: $ 1.58万
• 依托单位: VANDERBILT UNIVERSITY
• 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 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194462
• 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.

 描述（由申请人提供）：改善药物作用的预测药物的有效性各不相同，并会引起药物不良反应（ADR）。 ADR 在个人和社会层面造成重大成本，导致用药不依从、无效、毒性、住院和死亡。它们可以是“靶向”或“脱靶”，它们发生在各种治疗方法中，并且它们不仅对个体受试者和整个医疗保健系统中药物的使用方式产生重要且不断增加的影响，而且对新候选分子的开发方式也产生重要的、不断增加的影响。该卓越中心的主要目标是阐明药物作用和 ADR 变异性的新机制。我们为这项工作带来了一系列独特的新工具和资源，使我们能够自信地预测全新知识类别的快速发展，这将是当前缓慢、渐进进展规范的范式转变。项目 1 重点关注药物引起的 QT 间期延长，这是过去二十年药物重新贴标和停药的主要原因。传统观点将药物阻断“HERG 通道”作为主要机制，但我们提供了令人信服的数据，表明其他途径发挥着关键作用。我们将整合我们之前在该领域的基因组、分子、细胞和临床研究的结果，关于 P3 激酶在该 ADR 中的作用的令人兴奋的新数据，以及从我们已经建立的药物反应表型的个体中生成心肌细胞的能力，以开发新的范例来识别新候选药物和整个患者群体的风险。项目 2 重点关注免疫介导的 ADR，并使用来自药物过敏或药物耐受患者的独特细胞和 DNA 资源（面对特定的 HLA 风险等位基因）来定义 HLA 等位基因、特定 T 细胞受体的使用和严重 T 细胞介导的药物过敏之间的关联。我们的目标是测试药物超敏反应的新异源免疫模型，以解释这种表型变异并为新预测模型的开发提供信息。项目 3 将我们首创的全表组扫描新技术应用于拥有基因组和纵向电子病历数据的大量受试者，以广泛地重新调整药物的新适应症，并完善对长 QT 相关、HLA 相关和其他 ADR 的预测。因此，该中心的工作成果将推进我们的长期目标，即通过减轻 ADR 负担、改善个体受试者的预测、重新利用现有药物以及为药物开发过程提供新工具来降低 ADR 风险，从而改善药物治疗的结果。