Differential regulation of hypertrophy and apoptosis by beta adrenergic signaling in cardiac myocytes

翻译后摘要：β-肾上腺素能信号的肥大和凋亡的差异调节， 心肌细胞 心力衰竭是导致死亡的主要原因。β-肾上腺素能（βA）信号传导增加导致心力衰竭 通过心肌组织中的肥大和凋亡的同时但不同的调节。这些 联合反应导致心力衰竭前的病理性肥大。了解βA信号传导 差异调节肥大和凋亡信号网络可能产生新的治疗靶点， 治疗心力衰竭，也产生洞察机制的差异调节多个 通过单一刺激的表型。在目标1中，虽然先前的研究分别证明了β A诱导的 肥大或凋亡，这项建议将调查异质细胞的决策过程 之间的肥大和凋亡使用FRET生物传感器的凋亡活性和药理学和 对β A-肥大-凋亡信号网络的遗传干扰。这种方法代表 一种新的实验范式，同时监测两种表型在单细胞水平。在目标2中， 该提案将重建并独立验证心脏βA的计算模型， 肥大-凋亡信号网络，以发展对差异调节的机制性理解 细胞肥大和凋亡。总的来说，这些研究既是假设检验，也是假设生成 我希望这些研究能够确定和验证新的药理学靶点，以改善对 心衰

Abstract: Differential regulation of hypertrophy and apoptosis by beta adrenergic signaling in cardiac myocytes. Heart failure is the leading cause of death. Increased beta-adrenergic (βA) signaling contributes to heart failure through simultaneous yet differential regulation of hypertrophy and apoptosis in myocardial tissue. These combined responses result in pathologic hypertrophy preceding heart failure. Understanding how βA signaling differentially regulates the hypertrophic and apoptotic signaling networks may yield new therapeutic targets for treatment of heart failure and also yield insight into the mechanism of differential regulation of multiple phenotypes by a single stimulus. In Aim 1, while previous studies have separately demonstrated βA-induced hypertrophy or apoptosis, this proposal will investigate the heterogeneous cell decision-making process between hypertrophy and apoptosis using FRET biosensors of apoptotic activity and pharmacological and genetic perturbations to the combined βA-hypertrophic-apoptotic signaling network. This approach represents a novel experimental paradigm to simultaneously monitor both phenotypes at the single cell level. In Aim 2, this proposal will reconstruct and independently validate a computational model of the cardiac βA- hypertrophic-apoptotic signaling network to develop a mechanistic understanding of the differential regulation of hypertrophy and apoptosis. Collectively, these studies are both hypothesis-testing and hypothesis-generating and I expect these studies to identify and validate new pharmacological targets for the improved treatment of heart failure.