Novel Biomechanical Pathways in Cardiomyocyte Apoptosis

本研究的目的是研究机械应激抑制心肌细胞凋亡的细胞/分子机制。在美国，心力衰竭是导致残疾和死亡的主要原因。虽然人们已经认识到细胞凋亡发生在人类衰竭的心脏中，但机械应激在心肌细胞凋亡中的作用尚未明确。在这份奖学金提案中，我将检验机械应变通过机械激活的转录因子-核因子-kappaB(NF-kappaB)和信号转导和激活因子o转录因子3(STAT3)来抑制心肌细胞凋亡的总体假设。为了验证这一假设，我们将追求三个具体目标。目的1：探讨机械激活的核因子-kappaB和STAT3是否能抑制心肌细胞的凋亡。目的：探讨机械产生的活性氧(ROS)是否激活心肌细胞内的核因子-kappaB和信号转导通路3(STAT3)。目的：探讨机械激活的核因子-kappaB和信号转导通路3(STAT3)是否诱导心肌细胞中抗凋亡基因Bcl2家族成员Bclxl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.