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

描述(由申请人提供)：随着心力衰竭发病率的稳步增加，对新的治疗干预措施的调查是非常必要的。现已认识到，心肌细胞的不可逆性丢失与心功能不全和最终衰竭的进展有直接关系。虽然细胞死亡的两种主要类型--细胞凋亡和坏死--都有不同的形态特征，但只有细胞凋亡被认为是一种“程序性信号级联反应”。这一普遍的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是不确定的。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洞复合体，导致基质和膜间内容物的丢失。这一过程被称为线粒体通透性转换孔(MPTP)的形成，被认为是心力衰竭中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，但最近的发现，亲环素D是毛孔形成的主要调节因子，似乎指示着坏死性，而不是凋亡性细胞死亡，这为进一步了解这些过程打开了大门。因此，目前的提议试图验证以下中心假说：亲环素D介导的MPTP形成和随后的坏死性细胞死亡是推动心力衰竭发生和发展的主要机制。具体目标1将利用基因靶标小鼠确定亲环素D在心肌细胞进行性丧失和随后的心力衰竭发展中的作用。在一种经腹方法中，Aim 2将确定亲环素D特异性抑制剂Debio-025对MPTP的药理抑制是否能减少心力衰竭小鼠模型中的坏死细胞死亡。利用各种基因靶向的小鼠，结合对坏死性和凋亡性细胞死亡的仔细的分子评估，将寻求确定在临床相关的心力衰竭模型中坏死的贡献。 外行语言：随着心力衰竭迅速成为一种流行病，发现新的治疗方法势在必行。这项研究试图了解细胞死亡在心力衰竭进展中的核心作用。我们试图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通路。我们将利用从这项提议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。

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.