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（由申请方提供）：背景血小板活化和募集对于血管系统中血栓形成和血管闭塞至关重要，发生于血栓性急症，包括急性冠状动脉综合征（ACS）、卒中、深静脉血栓形成（DVT）和肺栓塞（PE）。在美国，血栓性急症对发病率和死亡率有很大的影响。有充分表征的血小板表面受体启动细胞内信号转导事件，触发血小板活化和血栓形成。这些受体中的一些在临床上被开发用于经历心肌梗死（MI）的患者的抗血小板药物。阿司匹林和氯吡格雷是两种用于治疗心肌梗死的抗血小板药物，但一项前瞻性研究显示，在阿司匹林基础上加用氯吡格雷，不良血管事件仅减少20%。在急性心肌梗死期间，可以使用支架打开冠状动脉。最近的数据表明，即使使用氯吡格雷和阿司匹林治疗，冠状动脉支架植入术也会导致约50%的患者出现“无复流”现象。无复流，即使在清除管腔阻塞后，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和观察到无复流有时会导致临床医生反射性地增加现有药物剂量，联合收割机抗血小板药物，或寻找针对相同血小板受体的新药，希望看到增强的疗效。创新观察另一种策略可能是考虑到血小板活性在疾病条件下有某种程度的不同（失调），如无复流和糖尿病，传统的抗血小板药物可能具有不可预测的影响。在缺血性微血管系统中，血小板暴露于富集浓度的活性氧（ROS），其可以独立于表面受体激活血小板。我们首次在血小板中发现了一种叫做ERK 5的蛋白质。ERK 5对ROS非常敏感，似乎是血小板缺血传感器，可触发适应不良的血小板行为。ERK 5是一种促分裂原活化蛋白激酶（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程。在无核血小板中，我们发现ERK 5对于正常血小板活化以及响应于ROS的血小板活化是重要的。使用活性氧和血小板激活剂大幅升高的小鼠心肌梗死模型，血小板特异性ERK 5-/-小鼠的梗死面积减少并改善心脏功能。此外，对血小板活化重要的蛋白质的表达和泛素化显著改变，表明可能存在将血小板转化为炎症性梗死后环境中的失调状态的开关。指导研究奖的重要性我治疗心血管疾病患者，因此我敏锐地意识到目前可用疗法的局限性和需求。传统上，血液学家对血小板研究做出了贡献，而心脏病学家通常开抗血小板药物。我的目标是在血栓基础研究和临床心血管护理的界面上操作。在开发用于心脏病发作患者的血小板抑制药物方面几乎没有进展，我认为这是因为对血小板功能失调还不了解。我建议从机制上证明血小板ERK 5作为“缺血传感器”的关键作用，MI后血小板活性失调的介体，以及血栓性急症的潜在新药靶点。本研究的初步数据代表了在定义MI后血小板功能方面的重大技术进步，并为药物治疗提出了新的相关血小板靶点。其目的是利用指导职业科学家奖，重点和发展独立的调查线需要启动作为一个医生科学家的职业生涯。为了实现这一目标，我将致力于表征缺血性损伤后ERK 5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，并以一种有凝聚力和有组织的方式补充我以前在生物化学和细胞信号传导方面的培训。