BETA-3 INTEGRIN TYROSINE PHOSPHORYLATION

描述：白细胞和血小板在血液中自由循环， 仅在炎症或血栓形成事件期间与血管壁相互作用。 b3家族的整合素介导许多白细胞和血小板粘附 在炎症消退和预防中重要的事件 失血过多该提案解决了b3整合素如何与细胞增殖和细胞凋亡相关的问题。 在循环中保持非粘性状态，以及它们如何成为 在疾病状态期间被激活以介导粘附事件。实验 在检验中详述了B3整联蛋白的组合事件 酪氨酸磷酸化和PKC活化都是白细胞和 血小板B3整合素活化。缺乏b3的白细胞 改变的小鼠将用正常或酪氨酸突变的B3整联蛋白重建 并评估其功能能力。类似地，细胞渗透肽 将用于破坏整合素-细胞骨架相互作用， 人巨噬细胞、血小板和嗜中性粒细胞的胞质面。 受体连接诱导的b3磷酸化，可能允许 与PKC相关的信号分子。实验包含在 本申请将确定候选分子RACK 1是否与 酪氨酸磷酸化的b3整合素并协调它们对PKC的反应 activation. 这些研究的完成将提高我们对b3整合素功能的认识 并为治疗操作提供新的靶点。 控制这种受体在临床上对预防 在自然病理学中可能发生的不必要的炎症和血栓形成 并且由于临床治疗，例如移植和血管移植， 手术

DESCRIPTION: Leukocytes and platelets circulate throughout the blood freely, interacting with vessel walls only during inflammatory or thrombotic events. Integrins of the b3 family mediate many of the leukocyte and platelet adhesive events which are important in the resolution of inflammation and the prevention of blood loss. This proposal addresses the question of how b3 integrins are maintained in a non-adhesive state in the circulation and how they become activated to mediate adhesive events during disease states. The experiments detailed within test the hypothesis that the combined events of b3 integrin tyrosine phosphorylation and PKC activation are both required for leukocyte and platelet b3 integrin activation. b3-deficient leukocytes from genetically altered mice will be reconstituted with normal or tyrosine mutant b3 integrins and their functional capabilities assessed. Similarly, cell-permeant peptides will be used to disrupt the integrin-cytoskeleton interaction on the cytoplasmic face in human macrophages, platelets, and neutrophils. Phosphorylation of b3 induced by receptor ligation, likely permits the association of signaling molecules responsive to PKC. Experiments contained in this application will determine if the candidate molecule RACK1 binds to tyrosine phosphorylated b3 integrins and coordinates their response to PKC activation. Completion of these studies will enhance our knowledge of b3 integrin function in hematopoietic cells and provide new targets for therapeutic manipulation. Control of this receptor is important clinically in the prevention of unwarranted inflammation and thrombosis which can occur in natural pathologies and as the result of clinical therapies such as transplantation and vascular surgery.