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）是人类的第一杀手。大多数CVD是关联的 动脉粥样硬化和血栓形成。越来越多的证据表明血小板是发起人 动脉粥样硬化和血栓形成。已知血小板中的激动剂刺激会激活 MAPK，已经证明它们对于体内和体内的血小板活动都很重要 体外。尽管MAPK信号传导有助于血小板功能，但 它们调节血小板活动的机制尚不完全了解。我们有 确定MAP3K家族的成员，凋亡信号调节激酶（ask1）是 存在于人类和鼠血小板中，并被生理激动剂激活。我们有 表明Ask1活动支持血小板聚集和分泌，以及Ask1的消融 赋予血栓形成体内模型的保护作用。因此，我们假设 血小板Ask1是动脉粥样硬化，动脉粥样硬化和缺血的关键调节剂 再灌注（I/R）损伤是由MI中的凝块溶解和中风造成的。我们也有 根据已发表的虚拟的信息确定了几种结构上不同的ASK1抑制剂 化学库屏幕。这些化合物中的两种在保护方面表现出极好的功效 血栓形成的小鼠对止血作用最小，通过尾巴出血时间和 激光诱导的止血模型。该R01提案的重点是描述血小板的作用 Ask1在开始动脉粥样硬化，动脉粥样硬化和加剧I/R损伤时。因此， 提出了三个具体目标。特定目标1将检验血小板的假设 Ask1是启动动脉粥样硬化的关键。我们将使用Hyperlipidemia鼠标模型（APOE - / - 小鼠 加入高脂饮食）以研究消融或抑制血小板Ask1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）期间的血小板激活。我们将使用 创新的小鼠模型以模仿牙菌斑破裂部位的血栓形成。具体的 AIM 3将测试血小板Ask1负责加重I/R损伤的假设。我们 将使用中风的瞬时脑动脉闭塞模型（TMCAO）评估 血小板Ask1消融/抑制对I/R损伤的影响。成功完成此建议 将有助于开发许多有关血栓形成疾病的治疗干预措施 例如动脉粥样硬化，MI和中风。