Genetic dissection of the platelet thrombohemorrhagic phenotype

血小板血栓出血表型的基因剖析

• 批准号: 8069931
• 负责人: Wadie F Bahou
• 金额: $ 39.25万
• 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/8069931
• 关键词: Address; Affect; Algorithms; Antiplatelet Drugs; Bioinformatics; Biological Models; Blood Platelet Disorders; Blood Platelets; Brain hemorrhage; Cardiovascular Diseases; Cells; Cerebrovascular Disorders; Coagulation Process; Communities; Computational Biology; Databases; Development; Diagnostic; Dissection; Equilibrium; Evolution; Gene Proteins; Genes; Genetic; Goals; Health; 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; Thrombotic Stroke; Transcript; Variant; cohort; disease classification; genetic profiling; interest; ischemic lesion; multidisciplinary; predictive modeling; prognostic; programs; 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，通常具有保护损伤免于出血后果的功能;此外，抗血小板药物是治疗心脑血管疾病的主要药物。尽管有这些基本的重要功能，但关于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很少。最近，我们的实验室已经证明，转录谱技术（在遗传解剖和恶性肿瘤的预测模型中发展良好）可以应用于血小板，并进行了必要的修改，旨在解决RNA产量和白细胞污染的限制。最近，我们已经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性后果相关的血小板疾病。由于与ET相关的血栓性表型是造血细胞限制性的（即血小板和/或白细胞），我们建议进一步发展这一主题，作为一个范例，用于识别血小板相关的分子签名，可能是血栓性或出血性中风的因果关系。我们现在建议吸收我们在血小板分析方面的专业知识，以最佳方式定义调节血栓出血平衡的血小板相互作用网络。一个在计算生物学、遗传学、止血和蛋白质组学方面具有相当专业知识的多学科团队已经组装起来专门开发这一主题。在具体目标1中，我们建议开发一个强大的平台，用于集成遗传和蛋白质组血小板分析;这一重点的子目标将是开发一个基于网络的，完全注释的界面，以广泛的研究社区感兴趣的集成血小板蛋白质组/转录组分析。在具体目标2中，我们将描述和表征区分血栓/出血表型的血小板基因和蛋白质的初始类别。在具体目标3中，我们将开发适用于较大队列的血栓出血分类预测和评分模型。这是可能的，综合蛋白质组学研究提出的背景下，这一建议将有更广泛的影响，脑血管或心血管疾病的患者的更大的子集，从而扩大未来的研究方向。公共卫生相关性：已知血小板调节凝血（血栓形成）和出血（出血），尽管只有有限数量的基因被确定控制这种平衡。在这项提案中，我们将开发和应用先进的血小板分析技术，以确定血小板基因，可能是因果关系的出血和血栓形成之间的平衡牵连。我们将研究人类血小板疾病（原发性血小板增多症）作为一个集中的模型系统，并作为基因被确定，应用该模型扩大患者队列。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。