The role of RASSF1A in myocardial ischemia/reperfusion injury

RASSF1A在心肌缺血/再灌注损伤中的作用

• 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
• 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

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）：缺血和再灌注（I/R）引起的坏死和凋亡导致的心肌细胞损失是导致心肌重塑和心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为急性心肌梗死患者提供有效的治疗方法。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，虽然心肌细胞的死亡在 I/R 过程中对心肌有害，但选择细胞的凋亡却是有益的。尽管是无菌环境，先天性和适应性免疫反应都会被心肌中的 I/R 激活。这很重要，因为精心策划的炎症反应对于清除碎片、激活修复细胞和促进 I/R 后伤口愈合是必要的。然而，过度和/或长期炎症会加剧基质降解，损害胶原沉积，导致更大的 CM 损失，扩大浸润至非梗塞心肌，增加纤维化并使心脏功能恶化。因此，维持平衡的炎症反应对于提供最大程度的心脏保护至关重要。因此，有理由认为，有缺陷的炎症细胞凋亡可能起到“故障刹车”的作用，并导致过度的免疫反应和恶化的损伤。 RASSF1A 是一种促凋亡分子和已知的肿瘤抑制因子，但关于 RASSF1A 和炎症的关系尚不清楚。我们的初步结果表明 RASSF1A 是 I/R 期间心肌炎症的重要调节剂。该提案将研究由于 RASSF1A 下调导致炎症细胞凋亡改变导致 I/R 后心肌损伤的可能性。我们假设，造血来源细胞中关键的内源性细胞凋亡信号级联的消除，即对细胞死亡的抵抗力增强，在 I/R 期间对心肌有害。为了检验我们的假设，我们将采用 WT 和 Rassf1A KO 小鼠的原代巨噬细胞培养物以及巨噬细胞细胞系来获得有关其体外激活和存活的机制见解。重要的是，这些研究将得到利用体内实验的补充 WT 和 KO 小鼠的骨髓移植和模拟 I/R。重要的是，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针对缺血性心脏病和急性心肌梗死的细胞类型特异性疗法。

项目成果

Erratum to: The hippo signaling pathway: implications for heart regeneration and disease.

勘误：河马信号通路：对心脏再生和疾病的影响。

• 发表时间: 2015
• 作者: Del Re; Dominic P
• 通讯作者: Dominic P

The hippo signaling pathway: implications for heart regeneration and disease.

河马信号通路：对心脏再生和疾病的影响。

• 发表时间: 2014-12
• 作者: Del Re; Dominic P
• 通讯作者: Dominic P