MECHANISM OF PLATELET ACTIVATION BY THE PEPTIDE LSARLAF

描述：本学术研究增强的长期目标 奖项提案旨在阐明由外向内信号的机制 由血小板纤维蛋白原受体，整合素介导的转导 alphaIIb-beta3。 外-内信号机制的解析 人血小板中的转导是重要的基础研究。 本研究 血小板的重要性不仅在于它在 心血管疾病，而且还因为洞察机制， 由外向内的信号转导对细胞生物学具有重要意义， 将军 深入了解由外向内信号的分子细节 血小板中的转导可能为设计一种 能够控制至少一些血小板行为的药剂 其有助于心血管疾病的发展和进展。 这项建议的长期目标将通过以下方式实现： 表征一种独特的受体活化肽对 血小板功能 这种受体激活肽似乎引起 血小板通过与α IIb结合而聚集， 纤维蛋白原受体的构象变化， 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是 旨在揭示受体激活肽如何与 受体使以前无活性的受体能够结合 纤维蛋白原，并确定纤维蛋白原结合是否是必要的， 受体的后续信号转导，或者如果后续信号 在没有纤维蛋白原引起的受体交联的情况下 或配体。 希望这些实验能揭示 受体内亚基或受体间相互作用， 血小板由外向内的信号转导反应。

DESCRIPTION: The long term objective of this Academic Research Enhancement Award 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- in 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 enables the previously inactive receptor to be able to bind fibrinogen and to determine if fibrinogen binding is necessary for subsequent signal transduction by the receptor or if subsequent signal transduction can occur in the absence of receptor crosslinking by fibrinogen or ligands. 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.