Novel Biomechanical Pathways in Cardiomyocyte Apoptosis

本研究旨在探讨机械应力抑制心肌细胞凋亡的细胞/分子机制。心力衰竭是美国残疾和死亡的主要原因。尽管已经认识到细胞凋亡发生在人类衰竭的心脏中，但机械应力在心肌细胞凋亡中的作用尚未明确定义。在这个奖学金的建议，我将测试的整体假设，机械应变抑制心肌细胞凋亡，通过机械激活的转录因子，核因子-κ B（NF-κ B B）和信号转导和转录激活因子3（STAT 3）。为了检验这一假设，将追求三个具体目标。目的1：探讨机械激活NF-κ B和STAT 3是否抑制心肌细胞凋亡。目的2：探讨机械性产生的活性氧（reactive oxygen species，ROS）是否激活心肌细胞NF-κ B和STAT 3。目标3：评估机械活化的NF-κ B和STAT 3是否诱导心肌细胞中Bcl-2家族的抗凋亡成员Bcl-xL的表达。

The goal of this proposal is to study the cellular/molecular mechanisms by which mechanical stress inhibits cardiomyocyte apoptosis. Heart failure is a leading cause of disability and death in the U.S. Although it has been recognized that apoptosis occurs in human failing hearts, the role of mechanical stress in cardiomyocyte apoptosis has not been clearly defined. In this fellowship proposal, I will test the overall hypothesis that mechanical strain inhibits cardiomyocyte apoptosis through mechanically activated transcription factors, nuclear factor-Kappa B (NF-kappaB) and signal transducer and activator o transcription 3 (STAT3). To test this hypothesis, three specific aims will be pursued. Aim 1 : To determine whether mechanically activated NF-kappaB and STAT3 inhibit apoptosis of cardiac myocytes. Aim 2: To explore whether mechanically generated reactive oxygen species (ROS) activate NF-kappaB and STAT3 in cardiomyocytes. Aim 3: To assess whether mechanically activated NF-kappaB and STAT3 induce the expression of Bcl-xL, an anti-apoptotic member of the Bcl-2 family, in cardiomyocytes.