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

整合素信号传导机制和新的抗血小板/抗炎方法

• 批准号: 10612047
• 负责人: Xiaoping Du
• 金额: $ 95.94万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612047
• 关键词: Acute; Adhesions; Adverse effects; Agonist; Amphotericin B; Anti-Inflammatory Agents; Anticoagulants; Antiplatelet Drugs; Aspirin; Atherosclerosis; Binding; Blood Platelets; Cardiovascular Diseases; Cause of Death; Cells; Chronic; Clinical; Coagulation Process; Cytoplasmic Tail; Disease; Family; Fibrin; GTP-Binding Proteins; Hemorrhage; Hemostatic function; Inflammation; Inflammatory; Integrins; Leukocytes; Life; Mediating; Morbidity - disease rate; Myocardial Infarction; Phagocytosis; Pharmaceutical Preparations; Play; Protein Subunits; Risk; Role; Sepsis; Signal Transduction; Site; Stroke; Thrombosis; Thrombus; adhesion receptor; cell motility; cytokine; mortality; novel strategies; prevent; response; thromboinflammation; thrombotic; transmission process; vascular injury

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.

血栓性心血管疾病仍然是美国和世界范围内死亡的主要原因。血小板玩 在止血和血栓形成中发挥关键作用。血小板不仅粘附并聚集形成血栓 在血管损伤部位，血小板也促进凝血（形成纤维蛋白凝块）。两者均为血小板血栓 形成和凝血是血栓性疾病（例如血栓性疾病）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药物被开发出来并应用于临床。 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药物已 的不足。首先，抗血小板药和抗凝药的主要不良反应都是出血，这 可能会危及生命。此外，抗血小板药物在治疗凝血方面效果不佳，而且 反之亦然，但抗血小板剂和抗凝剂的联合使用会大大加剧出血风险。这样一来，就会 开发不引起出血的双重抗血小板和抗凝药物具有重要意义。 此外，慢性和急性炎症性疾病（例如动脉粥样硬化）也可能诱发血栓形成 和败血症。相反，血栓形成会诱发并加剧炎症。因此，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 粘附受体家族在血小板和白细胞中发挥着关键作用。血小板整合素 aIIbb3 (GPIIb- IIIa)，在激动剂刺激的由内向外信号传导激活后，不仅介导血小板粘附， 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，但对于初步止血是可有可无的。白细胞 b2 整合素、aLb2 和 amb2 介导 白细胞粘附和由外向内的信号传导，导致细胞迁移、细胞因子释放、吞噬作用等，以及 因此在炎症中发挥关键作用。我们最近表明整合素的由外向内信号传导需要 G 蛋白亚基 Ga13 与 b2 和 b3 细胞质结构域中保守的 ExE 基序结合。 该提案的项目 1 是研究 Ga13 依赖性整合素由外向内信号传导的机制。 项目 2 是研究 b3 由外向内信号传导在剪切和激动剂诱导的血小板中的重要作用 促凝血活性，以及​​针对 Ga13-b3 相互作用开发双重抗凝血剂的概念基础 出血风险最小的血小板/抗凝药物。项目3是研究Ga13依赖的b2的作用 整合素从外到内信号传导在白细胞促炎功能和严重脓毒症中的作用，以及 开发治疗严重脓毒症的双重抗血栓和抗炎药物的概念基础 和其他血栓炎症性疾病。