Platelet Systems Biology in Health and Disease

描述（由申请人提供）：本文总结的建议通过以下方式响应PAR-12-138：（1）开发和获得血小板功能反应作为在系统生物学框架内研究的独特人类模型，（2）开发用于评估在一个稳健的系统中遗传序列变异的功能解释的新原理， 表型人群，和（3）开发整合的数学模型，包括遗传变异/基因表达研究，用于系统分析与复杂人类表型（血小板相关血栓性疾病，如脑/心血管疾病）相关的相关表型（血小板功能）。通过直接比较和开发使用正常和患病血小板群体的这些模型系统，增强了影响。血小板通过粘附和聚集事件介导止血的最初第一步，另外提供接触阶段和凝血级联反应传播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（即脑和心血管疾病）中至关重要，并继续在药物开发中进行深入研究，这是基于抗血小板药物在急性和预防性（一级和二级预防）环境中的充分记录的疗效。使用各种血小板活化模型的数据清楚地表明，血小板对大多数（如果不是全部）激动剂的反应在不同的浓度范围内是高度可变的。 支持在系统生物学框架内研究血小板功能反应的概念，该框架整合了与整体血小板反应相关的数量性状位点（QTL）和基因网络。在这个应用程序中，我们建议关闭目前存在的知识差距之间的进展，血小板遗传学和血小板功能的遗传基础，假设血小板功能反应可以开发为强大的模型，在正常和患病人群的综合遗传系统的发展。在具体目标1中，我们将在明确定义的正常和血小板增多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;在具体目标2中，我们建议开发整合的数学算法，将基因型变异和途径连接到健康和患病血小板的功能性血小板反应的预测模型中。该提案建立在长期的基础设施，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（Rev. 6/09）

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