DEFINING THE ROLE OF NECROTIC CELL DEATH IN THE PROGRESSION OF HEART FAILURE

定义坏死细胞死亡在心力衰竭进展中的作用

基本信息

批准号：
7486516
负责人：
John William Elrod
金额：
$ 4.68万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-28 至 2010-07-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7486516
关键词：
Accounting Adrenergic Agents Adult Affect Apoptosis Apoptotic Automobile Driving Binding Calcineurin Cardiac Cardiac Myocytes Cardiomyopathies Cell Death Cessation of life Chemicals Clinical Treatment Clinical Trials Complex Coupled Cyclophilins Cyclosporine Cyclosporins Development Disease Doxorubicin Drug Design Epidemic Etiology Evaluation Event Exhibits Failure Functional disorder Gene Targeting Genes Heart Heart Diseases Heart failure Hepatitis C Human Immunosuppressive Agents Incidence Investigation Knockout Mice Knowledge Language Lead Left Mediating Mitochondria Modeling Molecular Mus Muscle Cells Myocardial Infarction Nature Necrosis Numbers Organelles Outer Mitochondrial Membrane Pathogenicity Peptidylprolyl Isomerase Phase Play Process Protein Overexpression Relative (related person)Role Signal Pathway Signal Transduction Stimulus Testing Therapeutic Intervention Thinking Transgenic Mice Ventricular Function adrenergic analog cardiogenesis cell type clinically relevant cyclophilin D defined contribution heart cell inhibitor/antagonist insight mitochondrial permeability transition pore novel novel therapeutics pressure programs translational study

项目摘要

DESCRIPTION (provided by applicant): With the incidence of heart failure steadily increasing the investigation into novel therapeutic interventions is in great demand. It is now understood that there is a direct correlation between the irreversible loss of cardiomyocytes and the progression of cardiac dysfunction and eventual failure. While both major types of cell death, apoptosis and necrosis, have distinct morphological features only apoptosis has been viewed as exhibiting a 'programmed signaling cascade.' This general dogma has left the understanding of necrosis and its role in many pathogenic states largely undefined. A primary event in mitochondrial-mediated cell death is the formation of a pore complex spanning the inner and outer mitochondrial membranes resulting in the loss of matrix and intermembrane contents. This process is known as mitochondrial permeability transition pore (MPTP) formation and is viewed as a primary mechanism of cell death resulting from a number of pathogenic stimuli prominent in heart failure. While the exact constituents of the MPTP remain unclear, the recent discovery that cyclophilin D is a master regulator of pore formation and seemingly indicative of necrotic, as opposed to apoptotic cell death, has opened the door allowing further understanding of these processes. Therefore, the current proposal seeks to test the following central hypothesis: Cyclophilin Dmediated MPTP formation and subsequent necrotic cell death is a primary mechanism driving the development and progression of heart failure. Specific aim 1 will determine the role of cyclophilin D utilizing gene-targeted mice in the progressive loss of cardiomyocytes and subsequent development of heart failure. In a translatinal approach, aim 2 will determine if pharmacologic inhibition of MPTP with the cyclophilin Dspecific inhibitor, DEBIO-025, reduces necrotic cell death in murine models of heart failure. The utilization of various gene-targeted mice coupled with the careful molecular evaluation of necrotic vs. apoptotic cell death will seek to define the contribution of necrosis in clinically relevant models of heart failure. Lay language: With heart failure quickly becoming an epidemic it is imperative that new therapies are discovered. This study seeks to understand the central role of cell death in the progression of heart failure. We seek to define specific signaling pathways that lead to the death of heart cells and the subsequent development of heart dysfunction. We will utilize the knowledge gained from this proposal in the application of novel drugs designed to target and interrupt cell death in the heart.

描述（由申请人提供）：随着心力衰竭的发生，对新型治疗干预措施的调查稳步增加。现在可以理解，心肌细胞的不可逆转损失与心脏功能障碍的进展与最终失败之间存在直接相关。虽然两种主要类型的细胞死亡，凋亡和坏死，但具有独特的形态特征，只有凋亡被视为表现出“编程信号级联”。这种一般的教条使对坏死及其在许多致病状态中的作用的理解在很大程度上不确定。线粒体介导的细胞死亡中的主要事件是形成横跨线粒体和外部线粒体膜的孔复合物，导致基质和膜间含量的损失。该过程称为线粒体通透性过渡孔（MPTP）形成，被视为由心力衰竭突出的许多致病性刺激引起的细胞死亡的主要机制。尽管MPTP的确切组成部分尚不清楚，但最近发现环磷脂D是孔形成的主要调节剂，并且看似表明坏死，而不是凋亡细胞死亡，这打开了大门，允许进一步了解这些过程。因此，当前的提案试图检验以下中心假设：环磷脂的形成和随后的坏死细胞死亡是推动心力衰竭发展和发展的主要机制。具体的目标1将确定利用靶向基因的小鼠在心肌细胞进行性丧失和随后心力衰竭发展的过程中的作用。在翻译方法中，AIM 2将确定用环磷脂DSPEXIFIC抑制剂DEBIO-025对MPTP的药理抑制是否会减少心力衰竭的鼠模型中坏死细胞死亡。对各种基因靶向小鼠的利用以及对坏死与凋亡细胞死亡的仔细分子评估的使用将旨在定义坏死在临床相关的心力衰竭模型中的贡献。外行语言：随着心力衰竭迅速成为流行病，必须发现新疗法。这项研究试图了解细胞死亡在心力衰竭发展中的核心作用。我们试图定义导致心脏细胞死亡和随后心脏功能障碍的特定信号通路。我们将利用该提案中获得的知识，用于应用旨在靶向和中断细胞死亡的新型药物。