Platelet ERK5 regulates myocardial infarct expansion

血小板 ERK5 调节心肌梗死扩张

• 批准号: 9263832
• 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/9263832
• 关键词: Acute; Acute myocardial infarction; Address; Affect; Agonist; Animal Disease Models; Antiplatelet Drugs; Arteries; Aspirin; Award; Awareness; 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; Drug Utilization; Embolism; Emergency Situation; Environment; Event; Failure; Family member; Goals; Hematologist; Hemorrhage; 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; Recruitment Activity; Reflex action; 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; cohesion; cost; experience; heart function; improved; improved functioning; innovation; mortality; new therapeutic target; novel; 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（由适用提供）：背景血小板激活和募集对于血栓形成和血管闭塞至关重要，该血栓形成和血管阻塞发生在血栓形成紧急情况下，包括急性冠状动脉综合征（ACS），中风，深静脉血栓形成（DVT）和肺栓塞（PE）。血栓形成紧急情况极大地有助于美国的发病率和死亡率，有良好的血小板表面受体引发了细胞内信号转导事件，这些事件会触发血小板激活和血栓形成。这些接收器中的一些接受临床探索，用于患有心肌梗塞（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MI的抗血小板药物，但一项前瞻性研究表明，将氯吡格雷添加到阿司匹林中仅提前降低了20％的降低。在急性MI期间，可以使用支架打开冠状动脉。最近的数据表明，在约50％的患者中，将冠状动脉固定在冠状动脉中，将冠状动脉和阿司匹林治疗铅置于“无反流”现象中。即使消除了腔反应，也没有回流涉及下游微血管反对 - 血小板最活跃的区域。抗血小板药物的衰竭和观察到没有回流的失败有时会导致临床医生反身增加现有的药物剂量，结合抗血域药物，或者针对同一血小板接收器寻找新药物，以期看到有效性增强。创新的观察结果另一种策略可能是考虑到血小板活动在疾病条件下有所不同（失调），例如没有回流和糖尿病，传统的抗血小板药物可能会产生无法预测的影响。在缺血性的微脉管系统中，血小板暴露于富集浓度的活性氧（ROS），可以激活与表面受体无关的血小板。我们首次确定了一种称为ERK5的血小板中的蛋白质。 ERK5对ROS完全敏感，并且似乎充当血小板缺血传感器，会触发适应不良的血小板行为。 ERK5是一种有丝分裂原激活的蛋白激酶（MAPK）家族成员，通常在增殖细胞中发现，因为它驱动细胞周期的进展。在Annucleate血小板中，我们发现ERK5对于响应ROS的正常血小板激活以及血小板激活很重要。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 - / - 小鼠具有降低的基础设施大小和改善的心脏功能。此外，对血小板激活重要的蛋白质的表达和泛素化发生了巨大变化，这表明可能有一个开关将血小板转化为炎症后，感染后环境中的失调状态。指导研究奖的重要性我治疗患有心血管疾病的患者，因此我敏锐地意识到目前可用的治疗的局限性和需求。传统上，血液学家为血小板研究做出了贡献，而心脏病专家通常开了抗血小板药物。我的目标是基本血栓形成研究和临床心血管护理的界面。在患有心脏病发作的患者中，血小板抑制药物的发展几乎没有进步，我觉得这是因为不了解血小板功能失调。我建议将血小板ERK5作为“缺血传感器”，MI后血小板活性失调的介体以及潜在的新药物靶标的机械作用。这项研究的初步数据代表了在MI后定义血小板功能以及提出药物治疗的新相关血小板靶标方面的显着技术进步。旨在利用修改职业科学家奖的重点，并开发独立的调查线，以启动作为物理科学家的职业。为了实现这一目标，我将旨在表征ERK5在缺血性损伤后调节体内血小板激活的机制。这将使我能够学习以前无法访问的疾病动物模型，并以凝聚力和有条理的方式补充我先前在生物化学和细胞信号传导方面的培训。