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。血小板发挥作用 在止血和血栓形成中的关键作用。血小板不仅粘附并聚集在 血小板的血管损伤部位也有助于凝血（形成纤维蛋白凝块）。两个血小板血栓 形成和凝结是导致血栓性疾病的发病率和死亡率的重要因素 作为心脏病发作和中风。因此，开发了抗血小板药物和抗凝剂，并在临床上是 用于预防和治疗血栓形成。但是，当前的抗血域药物和抗凝剂具有 缺陷。首先，抗血小板药物和抗凝剂均具有出血的主要不利作用，这是 可能是威胁生命的。此外，抗血小板药物在治疗凝结方面不那么有效，并且恶化 Versa，但使用抗平台和抗凝剂的联合使用极大地加剧了出血风险。因此，会 对于开发双重抗血小板和抗凝药物，这不会引起出血，这是非常重要的。 此外，血栓形成可以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，血栓形成会诱导并加剧炎症。因此，这也是非常希望的 开发一种比阿司匹林在抗栓性和抗炎功效中更有效的药物。整合素 粘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），在激动剂刺激的内而外信号激活后，不仅介导了血小板粘附和 血栓形成，但也会传输外部信号，导致血栓膨胀和闭塞 血栓形成，但对于原发性止血是可分配的。白细胞B2整合素，Alb2和Amb2，中介 白细胞粘附和外部信号传导，导致细胞迁移，细胞因子释放，吞噬作用等，以及 因此在炎症中起关键作用。我们最近表明，整联蛋白的外部信号传导需要 G蛋白亚基Ga13与B2和B3的细胞质结构域保守的EXE基序的结合。 该提案的项目1是研究GA13依赖性整合素外部信号传导的机制。 项目2是研究B3外部信号传导在剪切和激动剂引起的血小板中的重要作用 Procagulant活性，以及​​针对GA13-B3相互作用的概念基础，以发展双重抗 血小板/抗凝蛋白药物具有最小的出血风险。项目3是为了研究GA13依赖性B2的作用 整联蛋白在白细胞和严重败血症的促炎功能中的外部信号传导以及 开发双重抗栓性和抗炎药的概念基础用于治疗严重败血症 和其他血栓炎症条件。