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Mitochondrial Permeability Transition as a Target for Cardioprotection in Heart F

线粒体通透性转变作为心脏 F 心脏保护的目标

基本信息

批准号：
9053516
负责人：
Sabzali Javadov
金额：
$ 29.31万
依托单位：
UNIVERSITY OF PUERTO RICO MED SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-22 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9053516
关键词：
5&apos -AMP-activated protein kinase Acetylation Adenine Nucleotide Translocase Affect Aftercare Animal Model Apoptosis Biogenesis Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cell Death Cell model Cells Collagen Complex Cyclosporine Development Diagnosis Down-Regulation Effector Cell Equilibrium Evolution Extracellular Matrix Fibroblasts Fibrosis Financial compensation Genetic study Heart Heart Diseases Heart Hypertrophy Heart failure Hypertrophy Immunosuppressive Agents Infarction Inflammation Injury Inner mitochondrial membrane Ischemia Ischemic Preconditioning Lead Life Mediating Metabolic Mitochondria Modeling Molecular Morbidity - disease rate Myocardial Myocardial Infarction Myocardial dysfunction Necrosis Outer Mitochondrial Membrane PPAR alpha Pathway interactions Patients Permeability Peroxisome Proliferator-Activated Receptors Play Prevention Propofol Proteins Rattus Regulation Reperfusion Therapy Role Signal Pathway Signal Transduction Signaling Molecule Techniques Testing Translating United States Ventricular Remodeling Voltage-Dependent Anion Channel Workload attenuation cyclophilin D experience genetic regulatory protein in vitro Model in vivo in vivo Model inhibitor/antagonist mitochondrial dysfunction mitochondrial permeability transition pore mortality novel therapeutic intervention prevent protective effect response sanglifehrin A stressor targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Cardiac remodeling following myocardial infarction is the initial myocardial hypertrophic response which follows myocardial injury and the eventual evolution to heart failure. Attenuation of the early adaptive hypertrophy can be translated into attenuation of heart failure response such that understanding the molecular and cellular mechanisms underlying progression of cardiac remodeling to heart failure is of crucial importance. Mitochondrial dysfunction is central to the loss of contractile function during ventricular remodeling/heart failure that are thought to be induced as a result of inactivation of cell signaling molecules, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha (PGC-1alpha). Mitochondrial permeability transition pore (MPTP) opening has been shown to be an end-effector for cell death that is associated with increased mitochondrial fragmentation due to alterations in the balance between fission and fusion of mitochondria. In this proposal, we hypothesize that the alterations in the AMPK/PGC-1alpha cascade trigger MPTP opening leading to cardiac dysfunction in post-infarction cardiac remodeling; modulation of the MPTP occurs through a direct interaction of AMPK/PGC-1alpha with the pore complex and/or indirectly, through AMPK-induced acetylation of cyclophilin D. To test our hypothesis we will study the intact heart, cultured cardiomyocytes and isolated mitochondria using an in vivo rat model of post-infarction remodeling and an in vitro model of rat cardiomyocyte hypertrophy. We have extensive experience with the proposed animal and cell models, and the necessary techniques to study mitochondrial function in cardiac diseases, and develop new pharmacological and conditional strategies for cardioprotection. The specific aims of this proposal are to: (1) Examine whether progression of post-infarction remodeling to heart failure is associated with increased MPTP opening and mitochondrial fragmentation; (2) Determine whether MPTP formation is regulated by the AMPK/PPARalpha pathway in cardiac remodeling; (3) Define whether inhibition of MPTP has long-term protective effects during post-infarction remodeling. The proposed studies will identify the specific mitochondrial adaptations and alterations, and help develop new therapeutic strategies for treatment of post-myocardial infarction heart failure.

描述（由申请人提供）：心肌梗死后的心脏重构是心肌损伤后的初始心肌肥厚反应，最终演变为心力衰竭。早期适应性肥厚的衰减可以转化为心力衰竭反应的衰减，因此了解心脏重构进展到心力衰竭的分子和细胞机制至关重要。在心室重构/心衰期间，线粒体功能障碍是收缩功能丧失的核心，这被认为是由于细胞信号分子，amp活化蛋白激酶（AMPK）和过氧化物酶体增殖体活化受体（PPAR）共激活因子-1 α (pgc -1 α)失活而诱导的。线粒体通透性过渡孔（MPTP）的开放已被证明是细胞死亡的一个末端执行器，由于线粒体分裂和融合之间的平衡改变，导致线粒体分裂增加。在本研究中，我们假设AMPK/ pgc -1 α级联的改变触发MPTP开放，导致梗死后心脏重构中的心功能障碍；MPTP的调节是通过AMPK/PGC-1alpha与孔复合物的直接相互作用和/或间接通过AMPK诱导的亲环蛋白d的乙酰化来实现的。为了验证我们的假设，我们将使用大鼠梗死后重构的体内模型和大鼠心肌细胞肥大的体外模型研究完整的心脏、培养的心肌细胞和分离的线粒体。我们在提出的动物和细胞模型方面有丰富的经验，以及必要的技术来研究线粒体在心脏病中的功能，并开发新的药物和条件策略来保护心脏。本研究的具体目的是：(1)研究梗死后重构向心力衰竭的进展是否与MPTP开放和线粒体断裂增加有关；(2)确定心脏重构过程中MPTP的形成是否受AMPK/ ppar通路的调控；(3)明确抑制MPTP在梗死后重构中是否具有长期保护作用。提出的研究将确定特定的线粒体适应和改变，并有助于制定新的治疗策略，治疗心肌梗死后心力衰竭。