Integrated molecular profiling 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 platelet-restricted, 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. In this exploratory R21 proposal, we now propose to assimilate our expertise in platelet transcriptomics to an expanded research focus in proteomics, with the long-term goal of optimally defining 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. Our collective experience and integrated platform for functional and molecular platelet analysis place our group in a unique position to complete these studies as outlined. While our initial studies have focused on a transcriptomic analysis of a rare platelet disorder (i.e. ET), 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 research direction.