BETA-3 INTEGRIN TYROSINE PHOSPHORYLATION

描述：白细胞和血小板在血液中自由循环， 仅在炎症或血栓事件期间与血管壁相互作用。 B3家族的整合素介导了许多白细胞和血小板的黏附 在消炎和预防方面具有重要意义的事件 失血过多。这项建议解决了b3整合素是如何存在的问题。 在循环中保持非粘连状态，以及它们是如何成为 被激活以在疾病状态下调节粘连事件。这些实验 在测试中详细说明了b3整合素的组合事件的假设 酪氨酸磷酸化和PKC激活都是白细胞和 血小板b3整合素活化。遗传来源的B3缺陷白细胞 改变的小鼠将用正常或酪氨酸突变的b3整合素重建 并对它们的功能能力进行评估。类似地，细胞内的多肽 将被用来干扰整合素-细胞骨架之间的相互作用 人巨噬细胞、血小板和中性粒细胞的胞浆面。 受体连接诱导的b3的磷酸化可能允许 对PKC作出反应的信号分子的联合。中包含的实验 这个应用程序将确定候选分子RACK1是否与 酪氨酸磷酸化b3整合素并协调其对PKC的反应 激活。 这些研究的完成将加强我们对b3整合素功能的认识。 并为治疗操作提供新的靶点。 对这种受体的控制在临床上对预防 自然病理中可能发生的不必要的炎症和血栓形成 作为移植和血管等临床治疗的结果 做手术。

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.