Platelet Systems Biology in Health and Disease

描述(申请人提供)：本提案是对PAR-12-138的回应：(1)发展和利用血小板功能反应作为一个独特的人体模型，在系统生物学的框架内进行研究；(2)发展新的原则以评估基因序列变异的功能解释。 (3)开发整合了遗传变异/基因表达研究的综合数学模型，用于系统分析与复杂的人类表型(如大脑/心血管疾病等与血小板相关的血栓性疾病)有关的表型(血小板功能)。通过使用正常和患病的血小板群体直接比较和开发这些模型系统，这种影响得到了增强。血小板通过黏附和聚集事件调节止血的最初第一步，另外提供接触阶段和凝血级联反应所需的带负电荷的磷脂表面。血小板在正常止血和病理性血栓形成(即脑部和心血管疾病)中起着至关重要的作用，并基于抗血小板药物在急性和预防性(一级和二级预防)环境中的良好疗效而继续在药物开发中进行深入研究。使用各种血小板激活模型的数据清楚地表明，血小板对大多数(如果不是全部)激动剂的反应在 支持在系统生物学框架内研究血小板功能反应的概念，该框架整合了数量性状基因座(QTL)和与整体血小板反应相关的基因网络。在这一应用中，我们建议弥合目前存在于血小板遗传学进展和血小板功能遗传基础之间的知识差距，假设血小板功能反应可以作为在正常和疾病人群中发展综合遗传系统的强大模型。在特定目标1中，我们将在明确定义的正常和血小板增多症队列中开发和表型量化遗传序列变异对血小板功能反应的影响；在特定目标2中，我们建议开发集成的数学算法，将基因变异和通路与健康和疾病的血小板功能反应的预测模型联系起来。这项建议建立在长期存在的基础设施、遗传数据库和专注于血小板生物学的跨学科合作的基础上，并将导致将遗传变异性与血小板和临床表型联系起来的新范式。PHS 416-9(6/09版)页面延续格式页面

DESCRIPTION (provided by applicant): The proposal summarized herewith is responsive to PAR-12-138 by (1) Developing and accessing platelet functional responses as a unique human model to be studied within the framework of systems biology, (2) development of novel principles for evaluating the functional interpretation of genetic sequence variation in a robustly phenotyped population, and (3) development of integrated mathematical models incorporating genetic variation/gene expression studies for systematic analysis of a relevant phenotype (platelet function) linked to a complex human phenotype (platelet-associated thrombotic disorders such as cerebo/cardiovascular disease, and. The impact is enhanced by directly comparing and developing these model systems using both normal and diseased platelet populations. Platelets mediate the initial first-step in hemostasis through adhesive and aggregatory events, additionally providing the negatively charged phospholipid surface required for the contact phase and propagation of the coagulation cascade. Platelets are fundamentally important in normal hemostasis and pathological thrombosis (i.e. cerebro- and cardiovascular disease), and continue to be intensely studied in drug development, predicated on the well-documented efficacy of antiplatelet agents in acute and preventative (both primary and secondary prophylaxis) settings. Data using various platelet activation models clearly demonstrate that platelet responses to the majority (if not all) agonists is highly variable within the population, supporting the concept of studying platelet functional responses within a systems biology framework that integrates quantitative trait loci (QTL) and gene networks linked to overall platelet responsiveness. In this application, we propose to close the knowledge gap currently existing between advances in platelet genetics and the genetic basis of platelet function, hypothesizing that platelet functional responses can be developed as powerful models for the development of integrated genetic systems in normal and diseased populations. In specific aim 1, we will develop and phenotypically quantify the impact of genetic sequence variants on platelet functional responses in well-defined normal and thrombocythemic cohorts; and in specific aim 2, we propose to develop integrated mathematical algorithms linking genotypic variants and pathways into predictive models of functional platelet responsiveness in healthy and diseased platelets. This proposal builds on long-standing infrastructure, genetic data bases, and interdisciplinary collaborations focusing on platelet biology, and will lead to novel paradigms linking genetic variability to platelet and clinical phenotypes. PHS 416-9 (Rev. 6/09) Page Continuation Format Page