MECHANISM OF PLATELETACTIVATION BY THE PEPTIDE LSARLAF

这一建议的长期目标是阐明由血小板纤维蛋白原受体，整合素αIIb/β3介导的由外向内信号转导的机制。阐明人血小板外信号转导的机制是重要的基础研究。这项研究之所以重要，不仅是因为血小板在心血管疾病中的中心作用，还因为深入了解外向内信号转导的机制对一般细胞生物学具有核心重要性。深入了解血小板由外向内信号转导的分子细节，可能为设计一种能够控制至少部分导致心血管疾病发生发展的血小板行为的药物提供理论基础。这项建议的长期目标将通过表征一种独特的受体激活肽对血小板功能的影响来实现。这种受体激活肽似乎通过与AlphaIIb结合从而引起纤维蛋白原受体的构象变化而引起血小板聚集，从而启动一系列血小板激活信号转导，最终导致“不可逆”的血小板聚集。这项建议中描述的实验旨在揭示受体激活肽与受体结合是如何引发由外向内的信号转导的。这些实验有望揭示启动外向内信号转导反应的受体内亚单位内或受体间相互作用的类型，并至少确定用于传播这种外向内信号转导的信号转导途径的轮廓。

The long term objective of this proposal is to elucidate the mechanism of outside-in signal transduction mediated by the platelet fibrinogen receptor, the integrin alphaIIb/beta3. Elucidation of the mechanism of outside-signal transduction in human platelets is important basic research. This research is important not only because of the central role of platelets in cardiovascular disease but also because insight into the mechanism of outside-in signal transduction is of central importance to cell biology in general. Gaining insight into the molecular details of outside-in signal transduction in platelets may provide a rationale for the design of a pharmaceutical agent able to control at least some of the platelet behavior which contributes to development and progression of cardiovascular disease. The long term objective of this proposal will be accomplished by characterizing the effects of a unique receptor activating peptide on platelet function. This receptor activating peptide appears to cause platelet aggregation by binding to alphaIIb and thereby eliciting a conformation change in the fibrinogen receptor which initiates a platelet activation signal transduction cascade that culminates in "irreversible" platelet aggregation. The experiments described in this proposal are designed to reveal how binding of the receptor activating peptide to the receptor elicits outside-in signal transduction. Hopefully, these experiments will reveal the type of intra- receptor subunit or inter-receptor interactions which initiate the outside-in signal transduction response in platelets and identify at least the outlines of the signal transduction pathway used to propagate this outside-in signal transduction.