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

摘要：β肾上腺素能信号对心肌细胞肥大和细胞凋亡的不同调节作用 心肌细胞。 心力衰竭是导致死亡的首要原因。β-肾上腺素能(βA)信号增强导致心力衰竭 通过对心肌组织肥大和细胞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信令如何 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，也有助于洞察多发性心力衰竭的辨证调控机制 由单一刺激产生的表型。在目标1中，虽然以前的研究分别证明了βA诱导 肥大或凋亡，这一建议将研究异质细胞的决策过程 利用FRET生物传感器检测细胞肥大和细胞凋亡之间的关系 βA-肥大-凋亡联合信号网络的遗传扰动。这种方法代表了 一种在单细胞水平上同时监测两种表型的新的实验范式。在目标2中， 这一建议将重建并独立验证心脏βA-的计算模型。 肥大-凋亡信号网络发展对差异调控的机制理解 肥大和细胞凋亡。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，以改善对慢性前列腺炎的治疗。 心力衰竭。

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.