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

家长助学金摘要： 血栓性心血管疾病仍然是美国和美国的主要死亡原因 世界。血小板在止血和血栓形成中都起着关键作用。不仅是因为 血小板在血管损伤处黏附和聚集形成血栓，但 血小板也有助于凝血(形成纤维蛋白凝块)。两种血小板血栓形成 形成和凝血是导致本病发病率和死亡率的重要因素。 血栓性疾病，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被临床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剂都存在不足。第一，反-- 血小板药物和抗凝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方面也没有那么有效。 凝血，反之亦然，但联合使用抗血小板和抗凝剂 极大地加剧了出血风险。因此，开发DUAL具有非常重要的意义 抗血小板和抗凝血药物，不会导致出血。此外， 血栓形成可由慢性和急性炎症条件引起，如 动脉粥样硬化和败血症。相反，血栓形成会诱发和加剧 发炎。因此，开发一种比这更有效的药物也是非常理想的 阿司匹林具有抗血栓和抗炎作用。黏附的整合素家族 受体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)，在激动剂刺激的由内向外信号激活时，不仅 介导血小板黏附和血栓形成，但也由外向内传递 导致血栓扩张和闭塞性血栓形成的信号，但对于 一次止血。白细胞𝛽2整合素、𝛼L𝛽2和𝛼m𝛽2介导白细胞 黏附和由外向内的信号，导致细胞迁移，细胞因子释放， 吞噬等，因此在炎症中起关键作用。我们最近展示了 整合素的自外向内信号需要G蛋白亚基G𝛼13与EXE结合 在𝛽2和𝛽3的细胞质区域中保守的基序。本提案的项目1 目的是研究G𝛼13依赖的整合素自外向内信号转导机制。 项目2是研究𝛽3外向内信号在剪切力和切变中的重要作用。 激动剂诱导的血小板促凝血活性及其靶向的概念基础 G-𝛼13-𝛽3相互作用开发具有最低限度抗血小板/抗凝血双重作用的药物 出血的风险。项目3是研究依赖G𝛼13的𝛽2整合素在细胞外的作用。 在白细胞的促炎功能和严重的脓毒症中的信号转导，以及 开发抗血栓和抗炎双重药物的概念基础 治疗严重的脓毒症和其他血栓炎症情况。

Abstract of Parent Grant: 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, but 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 𝛽2 integrins, 𝛼L𝛽2 and 𝛼m𝛽2, 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 G𝛼13 to an ExE motif conserved in the cytoplasmic domains of both 𝛽2 and 𝛽3. Project 1 of this proposal is to investigate the mechanisms of G𝛼13-dependent integrin outside-in signaling. Project 2 is to investigate the important role of 𝛽3 outside-in signaling in shear- and agonist-induced platelet procoagulant activity, and the conceptual basis for targeting G𝛼13- 𝛽3 interaction to develop a dual anti-platelet/anti-coagulant drug with minimal bleeding risk. Project 3 is to investigate the role of G𝛼13-dependent 𝛽2 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.