ASK1 a novel regulator of platelet function

ASK1 一种新型血小板功能调节剂

• 批准号: 10383745
• 负责人: ULHAS P NAIK
• 金额: $ 47.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383745
• 关键词: Ablation; Adhesions; Affect; Agonist; Antiplatelet Drugs; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Arteries; Atherosclerosis; Bleeding time procedure; Blood Platelets; Brain; Cardiovascular Diseases; Cessation of life; Coagulation Process; Coronary; Coronary heart disease; Data; Development; Disease; Dose; Drug Kinetics; Evaluation; Family; Family member; Genetic; Growth; Heart; Hemostatic function; High Fat Diet; Human; Hyperlipidemia; In Vitro; Integrins; Intervention; Ischemia; Ischemic Stroke; Lasers; MAP Kinase Gene; MAP Kinase Kinase Kinase; MAP3K5 gene; Middle Cerebral Artery Occlusion; Mitogen-Activated Protein Kinases; Modeling; Mus; Myocardial Infarction; Obesity; Obstruction; Pathogenesis; Pathway interactions; Pharmacodynamics; Phase III Clinical Trials; Phenotype; Phosphotransferases; Physiological; Plasma; Platelet Activation; Platelet aggregation; Play; Publishing; Reperfusion Injury; Reperfusion Therapy; Role; Rupture; Science; Signal Transduction; Signaling Molecule; Site; Specificity; Stroke; Tail; Testing; Therapeutic; Therapeutic Intervention; Thrombosis; Thrombus; Toxic effect; atherogenesis; atherosclerotic plaque rupture; atherothrombosis; base; cardiovascular disorder therapy; cerebral artery; combat; endothelial dysfunction; in vivo; in vivo Model; inhibitor; innovation; kinase inhibitor; member; mouse model; nonalcoholic steatohepatitis; novel; oxidized low density lipoprotein; platelet function; protective effect; receptor; response; small molecule inhibitor; small molecule libraries; stroke model; thrombotic complications; vascular injury; virtual

Cardiovascular disease (CVD) is the number one killer of mankind. Most CVDs are associated with atherosclerosis and thrombosis. Mounting evidence suggests that platelets are the initiators of both atherosclerosis and thrombosis. Agonist stimulation in platelets is known to activate MAPKs, and it has been shown that they are important for platelet activities both in vivo and in vitro. Despite this evident role of MAPK signaling contributing to platelet functions, the mechanisms through which they regulate platelet activities are not fully understood. We have identified that a member of the MAP3K family, apoptosis signal-regulating kinase (ASK1) is present in both human and murine platelets and is activated by physiological agonists. We have shown that Ask1 activity supports platelet aggregation and secretion, and ablation of Ask1 confers a protective effect in in vivo models of thrombosis. We therefore hypothesize that platelet ASK1 is a key regulator of atherogenesis, atherothrombosis, and ischemia reperfusion (I/R) injury resulting from clot dissolution in MI, and stroke. We have also identified several structurally distinct ASK1 inhibitors based on information from published virtual chemical library screens. Two of these compounds have shown excellent efficacy in protecting mice from thrombosis with minimal effects on hemostasis, as assessed by tail bleeding time and laser-induced hemostasis model. This R01 proposal is focused on delineating the role of platelet ASK1 in initiating atherogenesis, atherothrombosis, and aggravating I/R injury. Accordingly, three Specific Aims have been proposed. Specific Aim 1 will test the hypothesis that platelet ASK1 is key in initiating atherogenesis. We will use a hyperlipidemia mouse model (Apoe-/- mice fed with high-fat diet) to study the effect of ablation or inhibition of platelet Ask1 on plaque formation. Specific Aim 2 will test the hypothesis that platelet ASK1 is a central regulator of platelet activation during atherosclerotic plaque rupture (atherothrombosis). We will use an innovative mouse model to mimic thrombus formation at the site of plaque rupture. Specific Aim 3 will test the hypothesis that platelet ASK1 is responsible for aggravating I/R injury. We will use the transient middle cerebral artery occlusion model (tMCAO) of stroke to assess the effect of ablation/inhibition of platelet ASK1 on I/R injury. Successful completion of this proposal will help to develop a number of therapeutic interventions for thrombosis associated diseases such as atherosclerosis, MI, and stroke.

心血管疾病（CVD）是人类的第一杀手。大多数 CVD 都与 伴有动脉粥样硬化和血栓形成。越来越多的证据表明血小板是引发者 动脉粥样硬化和血栓形成。已知激动剂刺激血小板可激活 MAPKs，并且已经表明它们对于体内和体内的血小板活性都很重要 体外。尽管 MAPK 信号传导对血小板功能具有明显的作用，但 它们调节血小板活性的机制尚不完全清楚。我们有 确定 MAP3K 家族的成员凋亡信号调节激酶 (ASK1) 存在于人和鼠血小板中并被生理激动剂激活。我们有 显示 Ask1 活性支持血小板聚集和分泌，以及 Ask1 的消融 在体内血栓形成模型中具有保护作用。因此我们假设 血小板 ASK1 是动脉粥样硬化形成、动脉粥样硬化血栓形成和缺血的关键调节因子 心肌梗塞和中风中血栓溶解导致的再灌注 (I/R) 损伤。我们还有 根据已发布的虚拟信息，确定了几种结构不同的 ASK1 抑制剂 化学库屏幕。其中两种化合物在保护方面表现出优异的功效 通过尾部出血时间和评估，小鼠免受血栓形成对止血的影响最小 激光诱导止血模型。该 R01 提案的重点是描述血小板的作用 ASK1 启动动脉粥样硬化、动脉粥样硬化血栓形成和加重 I/R 损伤。因此， 提出了三项具体目标。具体目标 1 将检验以下假设：血小板 ASK1 是启动动脉粥样硬化形成的关键。我们将使用高脂血症小鼠模型（Apoe-/- 小鼠 高脂饮食喂养）研究血小板Ask1的消融或抑制对斑块的影响 形成。具体目标 2 将检验以下假设：血小板 ASK1 是 动脉粥样硬化斑块破裂（动脉粥样硬化血栓形成）期间血小板活化。我们将使用一个 创新的小鼠模型模拟斑块破裂部位的血栓形成。具体的 目标 3 将检验血小板 ASK1 导致 I/R 损伤加重的假设。我们 将使用中风的短暂性大脑中动脉闭塞模型（tMCAO）来评估 血小板 ASK1 的消融/抑制对 I/R 损伤的影响。圆满完成本次提案 将有助于开发一些针对血栓相关疾病的治疗干预措施 例如动脉粥样硬化、心肌梗死和中风。