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: 9894367
• 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/9894367
• 关键词: Acute; Adhesions; Adverse effects; Agonist; 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; 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的主要死亡原因。血小板游戏 止血和血栓形成的关键作用。血小板不仅粘附和聚集形成血栓， 在血管损伤部位，血小板也促进凝血（形成纤维蛋白凝块）。血小板血栓 形成和凝固是血栓性疾病的发病率和死亡率的重要因素 心脏病和中风因此，开发了抗血小板药物和抗凝剂，并在临床上用于治疗血小板减少症。 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 缺陷首先，抗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凝血方面并不有效， 反之亦然，但抗血小板和抗凝剂的联合使用大大加剧了出血风险。因此， 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，血栓形成可由慢性和急性炎症条件如动脉粥样硬化诱导 和败血症相反，血栓形成诱导和加剧炎症。因此，还高度期望的是， 开发一种在抗血栓和抗炎功效方面比阿司匹林更有效的药物。整联蛋白 粘附受体家族在血小板和白细胞中起关键作用。血小板整合素aIIbb 3（GPIIb- IIIa）在通过激动剂刺激的由内而外信号传导激活后，不仅介导血小板粘附， 血栓形成，而且还传递由外向内的信号，导致血栓扩张和闭塞。 血栓形成，但不适于主要止血。白细胞b2整联蛋白aLb 2和amb 2介导 白细胞粘附和由外向内信号传导，导致细胞迁移、细胞因子释放、吞噬作用等，和 因此在炎症中起关键作用。我们最近发现，整合素的由外向内信号传导需要 G蛋白亚基Ga 13与b2和b3的胞质结构域中保守的ExE基序的结合。 项目一是研究Ga 13依赖的整合素由外向内信号转导的机制。 项目二是研究b3 outside-in信号在剪切和激动剂诱导的血小板聚集中的重要作用。 促凝血活性，以及靶向Ga 13-b3相互作用以开发双重抗- 血小板/抗凝药物，出血风险最小。项目3是研究Ga 13依赖的b2在细胞内的作用。 在白细胞的促炎功能和严重脓毒症中的整合素外向内信号传导， 开发抗血栓和抗炎双重药物治疗严重脓毒症的概念基础 和其他血栓炎性病症。