Genetic dissection of the platelet thrombohemorrhagic phenotype

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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.