Improving Prediction of Drug Action

 描述（由申请人提供）：改善药物作用的预测药物是非常有效的，并引起药物不良反应（ADR）。药品不良反应在个人和社会层面上产生了重大成本，导致药物不依从、无效、毒性、住院和死亡。它们可以是“靶向”或“脱靶”的，它们发生在整个治疗范围内，并且它们不仅对药物在个体受试者和整个医疗保健系统中的使用方式，而且对新候选分子的开发方式具有重要且日益增加的影响。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，这将是一个范式转变，从目前的规范缓慢，渐进的进步。项目1的重点是药物引起的QT间期延长，这是过去二十年来药物重新标签和停药的主要原因。传统观点认为，药物阻断HERG通道是主要机制，但我们提供了令人信服的数据，表明其他途径也起着关键作用。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，激动人心的新数据P3激酶在这种ADR中的作用，以及从我们已经建立的药物反应表型的个体中产生心肌细胞的能力，以开发新的范例来识别新药候选人和患者人群的风险。项目2侧重于免疫介导的ADR，并使用来自药物超敏反应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细胞受体使用和严重T细胞介导的药物超敏反应之间的关联。我们的目标是测试一个新的异源免疫模型的药物过敏，以解释这种表型变异性，并告知新的预测模型的发展。项目3应用了我们在具有基因组和纵向电子病历数据的大型受试者队列中率先采用的全表型扫描新技术，以广泛地将药物重新用于新适应症，并改进对长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动我们的长期目标，即通过减少ADR负担，改善个体受试者的预测，重新利用现有药物，并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.