Mechanisms of integrin signaling and a new anti-platelet/anti-inflammatory approach

血栓性心血管疾病仍然是美国和世界上主要的死亡原因。血小板球 在止血和血栓形成中的关键作用。不仅是血小板黏附和聚集在一起形成血栓 在血管损伤的部位，血小板也促进凝血(形成纤维蛋白凝块)。两种血小板血栓形成 血栓形成和凝血是导致血栓性疾病发病率和死亡率的重要因素 如心脏病发作和中风。因此，抗血小板药物和抗凝血剂被开发出来，并在临床上应用 用于预防和治疗血栓形成。然而，目前的抗血小板药物和抗凝血剂已经 不足之处。首先，抗血小板药物和抗凝血剂都有出血的主要不良反应， 可能会危及生命。此外，抗血小板药物在治疗凝血方面不是那么有效，而且 反之亦然，但联合使用抗血小板和抗凝血剂极大地加剧了出血风险。因此，它将 开发不会导致出血的抗血小板和抗凝血双重药物具有重要意义。 此外，血栓形成可由慢性和急性炎症条件引起，如动脉粥样硬化。 还有败血症。相反，血栓形成会诱发和加剧炎症。因此，我们也非常希望 开发一种比阿司匹林更有效的抗血栓和抗炎药物。整合素 黏附受体家族在血小板和白细胞中都起着关键作用。血小板整合素aIIbb3(GPIIb- IIIA)，在激动剂刺激下由内向外信号激活时，不仅介导血小板黏附和 血栓形成，但也传递由外向内的信号，导致血栓扩张和闭塞 血栓形成，但对于初次止血是不必要的。白细胞b2整合素，aLb2和amb2，介导 白细胞黏附和由外向内信号，导致细胞迁移、细胞因子释放、吞噬等 因此在炎症中起着关键作用。我们最近发现整合素的自外向内信号需要 G蛋白亚基Ga13与b2和b3细胞质结构域中保守的Exe基序的结合。 该方案的第一个项目是研究依赖于Ga13的整合素自外向内信号转导的机制。 项目二是研究b3外向内信号在剪切剂和激动剂诱导的血小板中的重要作用。 促凝血活性，以及靶向Ga13-b3相互作用以开发双重抗凝血剂的概念基础 血小板/抗凝血剂，出血风险最小。项目3是研究依赖于Ga13的b2基因的作用。 整合素外-in信号在白细胞致炎功能和严重脓毒症中的作用 开发抗血栓和抗炎双重药物治疗严重脓毒症的概念基础 以及其他血栓炎症性疾病。

Thrombotic cardiovascular diseases remain the leading cause of death in US and world. Blood platelets play key roles in both hemostasis and thrombosis. Not only do platelets adhere and aggregate to form thrombi at the site of vascular injury, platelets also facilitate coagulation (formation of a fibrin clot). Both platelet thrombus formation and coagulation are important contributors to the morbidity and mortality of thrombotic diseases such as heart attack and stroke. Thus, anti-platelet drugs and anti-coagulants were developed and are clinically used to prevent and treat thrombosis. However, current anti-platelet drugs and anti-coagulants have deficiencies. First, anti-platelet drugs and anti-coagulants all have the major adverse effect of bleeding, which can be life-threatening. Furthermore, anti-platelet drugs are not as effective in treating coagulation, and vice versa, but combined use of anti-platelets and anti-coagulants greatly exacerbates bleeding risk. Thus, it would be highly significant to develop dual anti-platelet and anti-coagulant drugs, which do not cause bleeding. Furthermore, thrombosis can be induced by chronic and acute inflammatory conditions such as atherosclerosis and sepsis. Conversely, thrombosis induces and exacerbates inflammation. Thus, it is also highly desirable to develop a drug that is more potent than aspirin in anti-thrombotic and anti-inflammatory efficacy. The Integrin family of adhesion receptors plays key roles in both in platelets and leukocytes. Platelet integrin aIIbb3 (GPIIb- IIIa), upon activation by inside-out signaling stimulated by agonists, not only mediates platelet adhesion and thrombus formation, but also transmits outside-in signals leading to thrombus expansion and occlusive thrombosis, but is dispensable for primary hemostasis. Leukocyte b2 integrins, aLb2 and amb2, mediate leukocyte adhesion and outside-in signaling, leading to cell migration, cytokine release, phagocytosis, etc., and thus play critical roles in inflammation. We recently showed that outside-in signaling of integrins requires the binding of G protein subunit Ga13 to an ExE motif conserved in the cytoplasmic domains of both b2 and b3. Project 1 of this proposal is to investigate the mechanisms of Ga13-dependent integrin outside-in signaling. Project 2 is to investigate the important role of b3 outside-in signaling in shear- and agonist-induced platelet procoagulant activity, and the conceptual basis for targeting Ga13-b3 interaction to develop a dual anti- platelet/anti-coagulant drug with minimal bleeding risk. Project 3 is to investigate the role of Ga13-dependent b2 integrin outside-in signaling in proinflammatory functions of leukocytes and in severe sepsis, and the conceptual basis for developing dual anti-thrombotic and anti-inflammatory drugs for treating severe sepsis and other thrombo-inflammatory conditions.