Novel Biomechanical Pathways in Cardiomyocyte Apoptosis

本文的目的是研究机械应力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之一。尽管已经认识到人类衰竭的心脏会发生细胞凋亡，但机械应力在心肌细胞凋亡中的作用尚未明确定义。在本奖学金提案中，我将测试机械应变通过机械激活的转录因子、核因子- κ B （nf - κ B）和信号换能器和转录激活因子3 （STAT3）抑制心肌细胞凋亡的总体假设。为了验证这一假设，将追求三个具体目标。目的1：确定机械活化的NF-kappaB和STAT3是否抑制心肌细胞凋亡。目的2：探讨机械生成的活性氧（ROS）是否激活心肌细胞中的NF-kappaB和STAT3。目的3：评估机械激活的NF-kappaB和STAT3是否诱导心肌细胞中Bcl-xL （Bcl-2家族的抗凋亡成员）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.