Genetic dissection of the platelet thrombohemorrhagic phenotype

血小板血栓出血表型的基因剖析

• 批准号: 7749777
• 负责人: Wadie F Bahou
• 金额: $ 39万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7749777
• 关键词: Address; Affect; Algorithms; Antiplatelet Drugs; Bioinformatics; Biological Models; Blood Platelet Disorders; Blood Platelets; Brain hemorrhage; Cardiovascular Diseases; Cardiovascular system; Cells; Cerebrovascular Disorders; Coagulation Process; Communities; Computational Biology; Databases; Development; Diagnostic; Dissection; Equilibrium; Evolution; Future; Gene Proteins; Genes; Genetic; Goals; Hematopoietic; Hemorrhage; Hemorrhagic Disorders; Hemorrhagic Thrombocythemia; Hemostatic function; Human; Injury; Laboratories; Leukocytes; Malignant Neoplasms; Mediating; Methodology; Modeling; Modification; Molecular; Molecular Profiling; Online Systems; Pathway interactions; Patients; Phenotype; Principal Investigator; Proteomics; RNA; Research; Research Infrastructure; Risk; Stratification; Stroke; Techniques; Technology; Thrombosis; Transcript; Variant; cerebrovascular; cohort; disease classification; genetic profiling; interest; ischemic lesion; multidisciplinary; predictive modeling; prognostic; programs; public health relevance; tool; transcriptomics

DESCRIPTION (provided by applicant): Platelets are involved in the evolution of ischemic lesions, and normally function to protect from the hemorrhagic consequences of injury; furthermore, antiplatelet agents are the mainstays of treatment in cardiovascular and cerebrovascular disease. Despite these fundamentally important functions, very little information is available on the platelet genes and proteins that modulate the thrombohemorrhagic platelet phenotype. Recently, our laboratory has demonstrated that transcript profiling techniques (well-developed in genetic dissection and predictive models of malignancy) can be applied to platelets, with uniquely-developed modifications aimed at addressing limitations of RNA yield and leukocyte contamination. More recently, we have applied this approach to the study of essential thrombocythemia (ET), a platelet disorder frequently associated with thrombohemorrhagic consequences. Since the thrombohemorrhagic phenotypes associated with ET are hematopoietic cell-restricted (i.e. platelets and/or leukocytes), we propose to further develop this theme as a paradigm for identification of platelet-related molecular signatures that may be causally implicated in thrombotic or hemorrhagic stroke. We now propose to assimilate our expertise in platelet profiling to optimally define platelet interactive networks that regulate the thrombohemorrhagic balance. A multidisciplinary team with considerable expertise in computational biology, genetics, hemostasis, and proteomics has been assembled to specifically develop this theme. In specific aim 1, we propose to develop a robust platform for integrated genetic and proteomic platelet analyses; a subaim of this focus will be development of a web-based, fully-annotated interface of interest to the broad research community interested in integrated platelet proteomic/transcriptomic analyses. In specific aim 2, we will delineate and characterize an initial class of platelet genes and proteins that discriminate between the thrombo/hemorrhagic phenotype. In specific aim 3, we will develop class prediction and scoring models for thrombohemorrhage applicable to larger cohorts. It is likely that integrated proteomic studies proposed within the context of this proposal will have broader implications to the larger subsets of patients with cerebrovascular or cardiovascular disease, leading to an expanded future research direction. PUBLIC HEALTH RELEVANCE: Blood platelets are known to regulate clotting (thrombosis) and bleeding (hemorrhage), although only a limited number of genes have been identified that control this balance. In this proposal we will develop and apply sophisticated platelet profiling technologies to identify platelet genes that may be causally implicated in the balance between hemorrhage and thrombosis. We will study a human platelet disorder (essential thrombocythemia) as a focused model system, and as genes are identified, apply the model to expanded patient cohorts. These studies have wide-spread implications for larger numbers of patients who may suffer from cardiovascular disease and/or stroke.

描述（由申请人提供）：血小板参与缺血性病变的演变，并且通常具有保护免受损伤的出血后果的功能；此外，抗血小板药物是治疗心脑血管疾病的主要药物。尽管有这些重要的基本功能，但有关调节血栓出血性血小板表型的血小板基因和蛋白质的信息却很少。最近，我们的实验室已经证明，转录谱分析技术（在遗传解剖和恶性肿瘤预测模型方面得到了充分发展）可以应用于血小板，并进行了独特的修改，旨在解决 RNA 产量和白细胞污染的限制。最近，我们将这种方法应用于原发性血小板增多症（ET）的研究，这是一种经常与血栓出血后果相关的血小板疾病。由于与 ET 相关的血栓出血表型是造血细胞限制的（即血小板和/或白细胞），因此我们建议进一步开发这一主题，作为识别可能与血栓性或出血性中风有因果关系的血小板相关分子特征的范例。我们现在建议吸收我们在血小板分析方面的专业知识，以最佳地定义调节血栓出血平衡的血小板相互作用网络。一支在计算生物学、遗传学、止血学和蛋白质组学方面拥有丰富专业知识的多学科团队已经组建起来，专门开发这个主题。在具体目标 1 中，我们建议开发一个强大的平台，用于整合遗传和蛋白质组血小板分析；这一重点的一个子目标是开发一个基于网络的、有完整注释的界面，供对血小板蛋白质组/转录组综合分析感兴趣的广大研究界感兴趣。在具体目标 2 中，我们将描述和表征区分血栓/出血表型的初始类别的血小板基因和蛋白质。在具体目标 3 中，我们将开发适用于更大队列的血栓出血类别预测和评分模型。在本提案的背景下提出的综合蛋白质组学研究可能会对更大的脑血管或心血管疾病患者亚群产生更广泛的影响，从而扩大未来的研究方向。公共健康相关性：众所周知，血小板可以调节凝血（血栓形成）和出血（出血），尽管仅确定了有限数量的基因可以控制这种平衡。在本提案中，我们将开发并应用复杂的血小板分析技术来识别可能与出血和血栓形成之间的平衡有因果关系的血小板基因。我们将研究人类血小板疾病（原发性血小板增多症）作为一个重点模型系统，并在确定基因后，将该模型应用于扩大的患者群体。这些研究对大量可能患有心血管疾病和/或中风的患者具有广泛的影响。