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The role of RASSF1A in myocardial ischemia/reperfusion injury

RASSF1A在心肌缺血/再灌注损伤中的作用

基本信息

批准号：
8686259
负责人：
Dominic P Del Re
金额：
$ 15.9万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-26 至 2015-09-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8686259
关键词：
Ablation Acute Acute myocardial infarction Adenoviruses Antibodies Apoptosis Apoptotic Applications Grants Biochemistry Bone Marrow Bone Marrow Transplantation Breeding Cardiac Cardiac Myocytes Cell Death Cell Line Cells Cessation of life Cicatrix Collagen Data Dentistry Deposition Down-Regulation Environment Enzymes Equilibrium Exploratory/Developmental Grant Failure Fibrosis Funding Funding Mechanisms Future Genotype Goals Grant Heart Heart Diseases Hematopoietic High temperature of physical object Hour Housing Hurricane Immune response In Vitro Infarction Inflammation Inflammatory Inflammatory Response Injury Intention Intervention Investments Ischemia Lead Learning Macrophage Activation Measures Mediating Medical Medicine Molecular Morbidity - disease rate Mus Myocardial Myocardial Ischemia Myocardium Natural regeneration Necrosis New Jersey Operative Surgical Procedures Oxidative Stress Patients Play RNA Reagent Reperfusion Injury Reperfusion Therapy Resistance Resolution Role Sampling Signal Transduction Simulate Sterility Testing Time Tissue Sample Transfection Tumor Suppressor Proteins United States National Institutes of Health Universities Ventricular Remodeling Work Wound Healing base cell type effective therapy experience heart function improved in vivo inhibitor/antagonist insight macrophage mortality novel promoter public health relevance reconstitution research study response restriction enzyme scaffold therapeutic target tool

项目摘要

DESCRIPTION (provided by applicant): The loss of cardiomyocytes through necrosis and apoptosis in response to ischemia and reperfusion (I/R) is a critical factor leading to myocardial remodeling and loss of cardiac function. However, attempts at limiting cardiomyocyte death through broad-based inhibitors have yet to produce an effective treatment for patients with acute MI. We propose that this approach ignores the unique functionality and crosstalk that occurs between cell types and therefore fails to provide cardioprotection. In other words, while death of cardiomyocytes is deleterious to the myocardium during I/R, apoptosis of select cells is beneficial. Despite being a sterile environment, both innate and adaptive immune responses are activated by I/R in the myocardium. This is important because a well-orchestrated inflammatory response is necessary to clear debris, activate reparative cells and promote wound healing after I/R. However, excessive and/or prolonged inflammation can augment matrix degradation, impair collagen deposition, cause greater CM loss, extend infiltrate to non-infarcted myocardium, increase fibrosis and worsen heart function. Therefore, maintaining a balanced inflammatory response is critical to provide maximum cardioprotection. It is reasonable to posit, then, that defective inflammatory cell apoptosis could function as a "faulty brake" and cause an excessive immune response and worsened injury. RASSF1A is a pro-apoptotic molecule and known tumor suppressor, yet nothing is known regarding RASSF1A and inflammation. Our preliminary results implicate RASSF1A as an important modulator of inflammation in the myocardium during I/R. This proposal will examine the possibility that altered inflammatory cell apoptosis due to RASSF1A downregulation contributes to myocardial injury following I/R. We hypothesize that the ablation of a critical endogenous apoptotic signaling cascade, i.e. a heightened resistance to cell death, in cells of hematopoietic origin is detrimental to the myocardium during I/R. To test our hypothesis, we will employ the culture of primary macrophages from WT and Rassf1A KO mice and a macrophage cell line to attain mechanistic insight regarding their activation and survival in vitro. Importantly, these studies will be complimented by in vivo experiments utilizing bone marrow transplantation and simulated I/R in WT and KO mice. Importantly, the findings obtained upon successful completion of this proposal will have the potential to shift the medical paradigm away from general inhibitors of cell death toward cell type-specific therapies for ischemic heart disease and acute MI.

描述（由申请人提供）：响应缺血和再灌注（I/R）通过坏死和凋亡导致的心肌细胞损失是导致心肌重塑和心脏功能丧失的关键因素。然而，通过广泛的抑制剂限制心肌细胞死亡的尝试尚未产生对急性MI患者的有效治疗。我们认为这种方法忽略了细胞类型之间发生的独特功能和串扰，因此无法提供心脏保护。换句话说，虽然在I/R期间心肌细胞的死亡对心肌是有害的，但选择细胞的凋亡是有益的。尽管是无菌环境，先天性和适应性免疫应答都被心肌中的I/R激活。这一点很重要，因为精心策划的炎症反应是清除碎片、激活修复细胞和促进I/R后伤口愈合所必需的。然而，过度和/或长期的炎症可增加基质降解，损害胶原蛋白沉积，导致更大的CM损失，将浸润扩展到非梗死心肌，增加纤维化和恶化心脏功能。因此，维持平衡的炎症反应对于提供最大的心脏保护至关重要。因此，有理由认为，有缺陷的炎性细胞凋亡可能起到“故障刹车”的作用，导致过度的免疫反应和恶化的损伤。RASSF 1A是一种促凋亡分子和已知的肿瘤抑制因子，但关于RASSF 1A和炎症还一无所知。我们的初步结果表明RASSF 1A是I/R期间心肌炎症的重要调节剂。本研究将探讨RASSF 1A下调导致炎性细胞凋亡改变对I/R后心肌损伤的可能性。我们假设，在I/R期间，造血来源细胞中关键内源性凋亡信号级联的消融，即对细胞死亡的抵抗力增强，对心肌有害。为了验证我们的假设，我们将采用来自WT和Rassf 1A KO小鼠的原代巨噬细胞和巨噬细胞系的培养物，以获得关于其体外活化和存活的机制见解。重要的是，这些研究将得到体内实验的补充， WT和KO小鼠中的骨髓移植和模拟I/R。重要的是，在成功完成该提案后获得的发现将有可能将医学范式从细胞死亡的一般抑制剂转向缺血性心脏病和急性MI的细胞类型特异性疗法。