Improving Prediction of Drug Action

 描述(申请人提供)：提高对药物作用的预测药物有不同的效果，并引起药物不良反应(ADRs)。ADR在个人和社会层面上提取了主要成本，导致用药不合规、无效、毒性、住院和死亡。它们可以是“靶标上的”或“靶外的”，它们发生在各种治疗方法中，它们不仅对单个受试者和整个医疗系统使用药物的方式，而且对开发新的候选分子的方式产生了重要的且不断增加的影响。这个卓越中心的主要目标是阐明药物作用和不良反应的变异性背后的新机制。我们为这项工作带来了一组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，这将是对目前缓慢、渐进进展的规范的范式转变。项目1的重点是药物延长QT间期，这是过去20年来药物重新标记和停药的主要原因。传统的观点认为药物阻断是“HERG通道”的主要机制，但我们提出了令人信服的数据，即其他途径发挥了关键作用。我们将整合我们以前在该领域的基因组、分子、细胞和临床研究的结果，关于P3激酶在这种ADR中的作用以及我们已经建立的药物反应表型的个体产生心肌细胞的能力的令人兴奋的新数据，以开发新的范式来识别新药候选和患者群体中的风险。项目2专注于免疫介导的ADRs，并使用来自药物超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，以确定HLA等位基因、特定T细胞受体的使用与严重的T细胞介导的药物超敏之间的关系。我们的目标是测试一种新的药物超敏反应的异源免疫模型，以解释这种表型变异，并为新预测模型的发展提供信息。项目3将我们开创的新的表型扫描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，以广泛地重新使用药物以适应新的适应症，并改进对长QT相关、人类白细胞抗原相关和其他不良反应的预测。因此，该中心的工作成果将推进我们的长期目标，即通过减少ADR的负担、改善对单个对象的预测、重新利用现有药物以及为药物开发过程提供新的工具来降低ADR风险，从而改善药物治疗的结果。

 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.