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

心肌细胞中β肾上腺素信号传导对肥厚和凋亡的差异调节

基本信息

批准号：
9769126
负责人：
Bryan Chun
金额：
$ 5万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9769126
关键词：
Acute myocardial infarction Adrenergic Agents Adrenergic Antagonists Affect Apoptosis Apoptotic Area Biochemical Biological Assay Biosensor Cardiac Cardiac Myocytes Case Study Cause of Death Cells Cessation of life Clinical Complex Computer Analysis Computer Simulation Computing Methodologies Decision Making Differential Equation Equilibrium Fellowship Fluorescence Resonance Energy Transfer Future Genetic Growth Heart Heart failure Hypertrophy In Vitro Individual Intervention Knowledge Literature Logic Measures Methods Microscopy Modeling Molecular Monitor Morphology Myocardial tissue Myocardium Neonatal Pathologic Pathway interactions Pharmacology Phenotype Population Process Publishing Rattus Reaction Regulation Signal Pathway Signal Transduction Stimulus Stress Systems Biology Testing Therapeutic United States Validation Ventricular Work base experience experimental study heart cell improved in vivo insight live cell imaging mortality new therapeutic target novel predictive modeling response success therapeutic target

项目摘要

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.

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。