MECHANISM OF PLATELETACTIVATION BY THE PEPTIDE LSARLAF

本研究的长期目标是阐明血小板纤维蛋白原受体（整合素alphaIIb/beta3）介导的外向内信号转导机制。阐明血小板外信号转导的机制是一项重要的基础研究。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核心作用，还因为了解外向内信号转导的机制对细胞生物学具有重要意义。深入了解血小板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血小板行为的药物提供理论依据，这些行为有助于心血管疾病的发生和进展。该建议的长期目标将通过描述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结合引起血小板聚集，从而引起纤维蛋白原受体的构象改变，从而启动血小板激活信号转导级联，最终导致“不可逆”血小板聚集。本提案中描述的实验旨在揭示受体激活肽与受体的结合如何引发由外而内的信号转导。希望这些实验能够揭示血小板中启动外向内信号转导反应的受体内亚基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.