Platelet glycoprotein VI dependent microparticle formation

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DESCRIPTION (provided by applicant): (GP) VI is one of two major primary platelet receptors for collagen, a critical ligand at the interface of flowing blood and damaged vasculature. The relevance of GPVI to platelet function has been established with inhibitory antibodies, genetically modified mice, human genetic polymorphisms, and mutations. Stimulation of platelets with fibrillar collagen leads to platelet aggregation and a dramatic release of platelet microparticles (platelet fragments of less than 1 m). We will demonstrate the release of microparticles is mediated by ligand binding to platelet GPVI. Beyond the relevance of collagen to hemostasis and thrombosis, GPVI and the presence of platelet microparticles has recently been shown to exacerbate rheumatoid arthritis in murine models. The link to human disease is the presence of up to 400,000 platelet microparticles per l in diseased synovial fluid. As such, the platelet microparticle represents the major cellular component in synovial fluid from rheumatoid arthritis patients. Genetic deletion of GPVI or its associated subunit, FcR- , ameliorates disease in mouse models of rheumatoid arthritis. Variation in the number of platelet microparticles present in diseased human synovial fluid has been observed but the mechanistic basis or physiologic relevance for this variation is unknown. We propose addressing a major gap in the translation of GPVI biology to our understanding and treatment of rheumatoid arthritis. First, known GPVI haplotypes exist that effect GPVI-dependent signal transduction pathways. A gap exists in our understanding for whether and how platelet microparticles are influenced by specific GPVI haplotypes. Secondly, a major question exists as to whether GPVI expression and function can influence the severity of rheumatoid arthritis. To address these issues, we propose 1) to characterize platelet microparticle production from normal human samples of defined GPVI haplotypes and 2) document GPVI haplotypes in a cohort of patients with rheumatoid arthritis patients exhibiting disease from minimal to extreme severity. The outcome of the proposed studies could impact clinical practice paradigms for the treatment of rheumatoid arthritis with the possibility these mechanisms are relevant to other autoimmune-dependent inflammations, such as asthma. Thus, the proposed studies test novel hypotheses seeking to establish new paradigms linking hemostasis, thrombosis and inflammation.