Platelet ERK5 regulates myocardial infarct expansion

血小板 ERK5 调节心肌梗死扩张

• 批准号: 9109975
• 负责人: Scott James Cameron
• 金额: $ 15.51万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109975
• 关键词: Acute myocardial infarction; Address; Affect; Agonist; Animal Disease Models; Arteries; Aspirin; Award; Behavior; Biochemistry; Biological; Blood Platelets; Blood Vessels; Blood coagulation; Cardiac; Cardiovascular Diseases; Cardiovascular system; Caring; Cell Cycle Progression; Cells; Clinical; Complement; Coronary artery; Data; Deep Vein Thrombosis; Development; Diabetes Mellitus; Disease; Dose; Drug Targeting; Embolism; Emergency Situation; Environment; Event; Failure; Family member; Goals; Heart; Hematologist; Hemorrhage; Hemostatic function; Human; Infarction; Inflammation; Inflammatory; Investigation; Ischemia; Learning; Lung; MAPK7 gene; Mediating; Mediator of activation protein; Mentors; Microvascular Dysfunction; Mitogen-Activated Protein Kinases; Modeling; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Obstruction; Organ; Outcome; Patients; Performance; Perfusion; Pharmaceutical Preparations; Phenotype; Physicians; Physiology; Platelet Activation; Play; Process; Proliferating; Prospective Studies; Proteins; Quality of life; Reactive Oxygen Species; Research; Residual state; Role; Rupture; Scientist; Signal Transduction; Signal Transduction Pathway; Societies; Stents; Stroke; Surface; Therapeutic; Thrombosis; Thrombus; Time; Training; Ubiquitination; Ventricular Remodeling; Western World; acute coronary syndrome; base; blood vessel occlusion; career; clopidogrel; cost; experience; heart function; improved; improved functioning; innovation; mortality; new therapeutic target; novel; platelet typing; protein expression; public health relevance; receptor; response; sensor; stem; stroke treatment; targeted treatment

 DESCRIPTION (provided by applicant): Background Platelet activation and recruitment are critical for thrombus formation and blood vessel occlusion in the vasculature, occurring in thrombotic emergencies including acute coronary syndromes (ACS), stroke, Deep Vein Thrombosis (DVT), and Pulmonary Embolus (PE). Thrombotic emergencies contribute greatly to morbidity and mortality in the U.S. There are well-characterized platelet surface receptors initiating intracellular signal transduction events which trigger platelet activation and thrombus formation. Some of these receptors are exploited clinically using anti-platelet medications for patients who experience a myocardial infarction (MI). Aspirin and clopidogrel are two anti-platelet agents used to treat MI yet one prospective study showed only a 20% reduction in adverse vascular events with the addition of clopidogrel to aspirin. During an acute MI, coronary arteries can be opened using stents. Recent data indicates that stenting a coronary artery-even with clopidogrel and aspirin therapy-leads to a `no reflow' phenomenon in around 50% of patients. No reflow, even after removing luminal obstruction, is thought to involve downstream microvascular obstruction-a region where platelets are most active. Failure of anti-platelet medications and observing no reflow sometimes leads clinicians to reflexively increase the existing drug dose, to combine anti-platelet medications, or to search for new medications against the same platelet receptors in the hope of seeing enhanced efficacy. Innovative Observation Another strategy may be to consider that platelet activity is somehow different (dysregulated) in disease conditions such as no reflow and diabetes where traditional anti-platelet medications can have unpredictable effects. In the ischemic microvasculature, platelets are exposed to enriched concentrations of reactive oxygen species (ROS) which can activate platelets independent of surface receptors. We have, for the first time, identified a protein in platelets called ERK5. ERK5 is exquisitely sensitive to ROS, and appears to act as a platelet ischemic sensor, which triggers maladaptive platelet behavior. ERK5 is a Mitogen-Activated Protein Kinase (MAPK) family member usually found in proliferating cells because it drives cell cycle progression. In the anucleate platelet, we found that ERK5 is important for normal platelet activation as well as platelet activation in response to ROS. Using a mouse MI model in which ROS and platelet activators are greatly elevated, platelet specific ERK5-/- mice have reduced infarct size and improved heart function. In addition, the expression and ubiquitination of proteins important for platelet activation are dramatically altered, suggesting there may be a switch which transforms platelets into a dysregulated state in inflammatory, post-infarct environment. Importance of the Mentored Research Award I treat patients with cardiovascular disorders and so I am acutely aware of the limitations and needs of currently available therapeutics. Traditionally, hematologists have contributed to platelet research while cardiologists typically prescribe anti-platelet medications. I aim operate at the interface of basi thrombosis research and clinical cardiovascular care. There has been little advance in the development of platelet inhibiting drugs to use in patients with heart attack and I feel this is because dysregulated platelet function is not understood. I propose to mechanistically demonstrate a key role for platelet ERK5 as an `ischemia sensor', a mediator of dysregulated platelet activity following MI, and a potentially new drug target for thrombotic emergencies. The preliminary data for this study represents a significant technological advancement in terms of defining platelet function following MI as well as suggesting new relevant platelet targets for drug therapy. The aim to use the mentored career scientist award to focus and to develop independent lines of investigation needed to launch a career as a physician scientist. To achieve this goal I will aim to characterize the mechanism by which ERK5 regulates platelet activation in the body following an ischemic insult. This will allow me to learn animal models of disease previously inaccessible to me and to complement my previous training in biochemistry and cellular signaling in a cohesive and organized manner.

 描述（由申请人提供）： 背景 血小板活化和募集对于脉管系统中的血栓形成和血管闭塞至关重要，发生在包括急性冠脉综合征 (ACS)、中风、深静脉血栓形成 (DVT) 和肺栓塞在内的血栓紧急情况中。 PE）。在美国，血栓紧急情况对发病率和死亡率有很大影响。有充分表征的血小板表面受体启动细胞内信号。其中一些受体在临床上被用于治疗心肌梗死 (MI) 患者的抗血小板药物，阿司匹林和氯吡格雷是用于治疗 MI 的两种抗血小板药物。研究表明，在阿司匹林中添加氯吡格雷后，使用支架可以打开冠状动脉，仅可减少 20% 的不良血管事件。冠状动脉（即使使用氯吡格雷和阿司匹林治疗）也会导致约 50% 的患者出现“无复流”现象，即使在消除管腔阻塞后也不会发生复流，这被认为涉及下游微血管阻塞（血小板最活跃的区域）。抗血小板药物治疗失败且观察不到复流有时会导致本能地增加现有药物剂量，联合使用抗血小板药物，或寻找针对相同血小板受体的新药物以期看到增强的疗效。创新观察另一种策略可能是考虑血小板活性在疾病条件下存在某种不同（失调），例如无复流和糖尿病，传统抗血小板药物可能会产生不可预测的影响。氧自由基 (ROS) 可以独立于表面受体激活血小板 我们首次发现血小板中一种名为 ERK5 的蛋白质对 ROS 非常敏感，并且似乎可以发挥作用。作为血小板缺血传感器，它会触发血小板适应不良行为，ERK5 是一种丝裂原激活蛋白激酶 (MAPK) 家族成员，通常存在于增殖细胞中，因为它驱动细胞周期进展。血小板激活以及血小板激活对 ROS 的反应使用小鼠 MI 模型，其中 ROS 和血小板激活剂大大升高，血小板特异性 ERK5-/-小鼠的梗塞面积缩小，心脏功能得到改善，此外，对血小板活化重要的蛋白质的表达和泛素化发生了显着改变，这表明在炎症、梗塞后环境中可能存在将血小板转变为失调状态的转变。指导研究奖 我治疗心血管疾病患者，因此我敏锐地意识到当前可用疗法的局限性和需求。传统上，血液学家为血小板研究做出了贡献，而心脏病学家通常开出抗血小板药物。我的目标是结合基础血栓研究和临床心血管护理，在开发用于心脏病患者的血小板抑制药物方面进展甚微，我认为这是因为我对血小板功能失调的了解不够。提议从机制上证明血小板 ERK5 作为“缺血传感器”、心肌梗死后血小板活性失调的调节剂以及血栓紧急情况的潜在新药物靶点的关键作用。这项研究的初步数据代表了一项重要的技术。在定义心肌梗死后的血小板功能方面取得进展，并提出新的相关血小板药物治疗目标。目的是利用指导职业科学家奖来关注和开发开展医师科学家职业所需的独立研究路线。为了实现这一目标，我的目标是描述 ERK5 在缺血性损伤后调节体内血小板活化的机制，这将使我能够学习以前无法接触到的疾病动物模型，并补充我之前在生物化学和细胞信号传导方面的培训。一个有凝聚力和有组织的方式。