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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：
7783816
负责人：
John William Elrod
金额：
$ 5.01万
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/7783816
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 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 Organelles Outer Mitochondrial Membrane Pathogenicity Phase II Clinical Trials Play Process Relative (related person)Role Signal Pathway Signal Transduction Stimulus Testing Therapeutic Intervention 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 therapeutic intervention novel therapeutics overexpression 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）：随着心力衰竭发病率的稳步增加，迫切需要对新型治疗干预措施进行研究。现在人们了解到，心肌细胞的不可逆损失与心脏功能障碍和最终衰竭的进展之间存在直接相关性。虽然细胞死亡的两种主要类型（细胞凋亡和坏死）具有不同的形态学特征，但只有细胞凋亡被视为表现出“程序化信号级联”。这种普遍的教条使得人们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没有被定义。线粒体介导的细胞死亡的主要事件是跨越线粒体内膜和外膜的孔复合物的形成，导致基质和膜间内容物的损失。这一过程被称为线粒体通透性转换孔（MPTP）形成，被视为心力衰竭中多种致病刺激引起的细胞死亡的主要机制。虽然 MPTP 的确切成分仍不清楚，但最近发现亲环蛋白 D 是孔形成的主要调节剂，并且似乎表明细胞坏死，而不是细胞凋亡，这为进一步了解这些过程打开了大门。因此，当前的提议旨在检验以下中心假设：亲环蛋白D介导的MPTP形成和随后的坏死细胞死亡是驱动心力衰竭发生和进展的主要机制。具体目标 1 将确定利用基因靶向小鼠的亲环蛋白 D 在心肌细胞逐渐丧失和随后心力衰竭发展中的作用。在跨拉丁方法中，目标 2 将确定使用亲环蛋白 D 特异性抑制剂 DEBIO-025 对 MPTP 进行药理学抑制是否可以减少小鼠心力衰竭模型中的坏死细胞死亡。利用各种基因靶向小鼠，加上对坏死性细胞死亡与凋亡性细胞死亡的仔细分子评估，将试图确定坏死在临床相关心力衰竭模型中的作用。通俗语言：随着心力衰竭迅速成为一种流行病，迫切需要发现新的疗法。本研究旨在了解细胞死亡在心力衰竭进展中的核心作用。我们寻求定义导致心脏细胞死亡和随后发生心功能障碍的特定信号传导途径。我们将利用从该提案中获得的知识来应用旨在靶向和中断心脏细胞死亡的新药物。