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

描述（由申请人提供）：随着心力衰竭的发病率稳步上升，研究新的治疗干预措施的需求很大。现在了解到，心肌细胞的不可逆损失与心功能障碍的进展和最终衰竭之间存在直接关联。细胞凋亡和坏死这两种主要的细胞死亡类型都有不同的形态学特征，只有细胞凋亡被认为是一种“程序化的信号级联”。这一普遍教条使得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明确。线粒体介导的细胞死亡的一个主要事件是形成一个跨越线粒体内外膜的孔复合体，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过渡孔（MPTP）的形成，被认为是心衰中主要由许多致病刺激引起的细胞死亡的主要机制。虽然MPTP的确切成分尚不清楚，但最近发现亲环蛋白D是孔隙形成的主要调节剂，似乎表明坏死，而不是凋亡细胞死亡，这为进一步了解这些过程打开了大门。因此，目前的建议旨在验证以下中心假设：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。特异性目的1将利用基因靶向小鼠确定亲环蛋白D在心肌细胞进行性丧失和随后心力衰竭发展中的作用。在翻译方法中，目的2将确定MPTP与亲环蛋白d特异性抑制剂DEBIO-025的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，结合坏死与凋亡细胞死亡的仔细分子评估，将寻求确定坏死在心力衰竭临床相关模型中的作用。

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.