ASK1 a novel regulator of platelet function

ASK1 一种新型血小板功能调节剂

• 批准号: 9899282
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899282
• 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; Structure; 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/antagonist; 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; 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）是人类的头号杀手。大多数心血管疾病与 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 动脉粥样硬化和血栓形成。已知血小板中的激动剂刺激可激活 MAPKs，并且已经表明它们对于体内和体内血小板活性都是重要的。 体外尽管MAPK信号对血小板功能有明显的作用， 它们调节血小板活性的机制还不完全清楚。我们有 发现MAP 3 K家族成员凋亡信号调节激酶（ASK 1）是 存在于人和鼠血小板中，并被生理激动剂激活。我们有 显示Ask 1活性支持血小板聚集和分泌，以及Ask 1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ASK 1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 MI中的凝块溶解导致的再灌注（I/R）损伤和中风。我们还 根据已发表的虚拟实验室的信息， 化学文库筛选。这些化合物中的两种在保护 通过尾部出血时间评估，小鼠免于血栓形成，对止血的影响极小， 激光诱导止血模型。本R 01提案的重点是描述血小板的作用 ASK 1在启动动脉粥样硬化形成、动脉粥样硬化血栓形成和加重I/R损伤中的作用。因此，委员会认为， 提出了三个具体目标。具体目标1将检验血小板 ASK 1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），以研究血小板Ask 1的消融或抑制对斑块的影响 阵具体目标2将检验血小板ASK 1是血小板活化的中枢调节因子的假设。 动脉粥样硬化斑块破裂（动脉粥样硬化血栓形成）期间的血小板活化。我们将使用 创新的小鼠模型来模拟斑块破裂部位的血栓形成。具体 目的3将验证血小板ASK 1负责加重I/R损伤的假设。我们 将使用中风的短暂性大脑中动脉闭塞模型（tMCAO）来评估 消融/抑制血小板ASK 1对I/R损伤的影响。成功完成本提案 将有助于开发一些血栓形成相关疾病的治疗干预措施 如动脉粥样硬化、心肌梗塞和中风。