Proteomic Analysis of Beta Adrenergic Receptor Signaling

描述（由申请人提供）：心力衰竭是美国发病率和死亡率的主要原因。目前的心力衰竭模型假设神经体液激活有助于左心室功能障碍进展为临床心力衰竭。认为慢性β肾上腺素能受体刺激通过引起心肌细胞凋亡增加而导致心力衰竭。具体而言，β 1受体被认为与肌细胞中的促凋亡途径偶联。最近的研究表明，β 2受体也可能与促进心肌细胞存活的抗凋亡途径偶联。本项目的目标是使用称为反相蛋白（RPP）裂解物微阵列的蛋白质组学技术分析心肌细胞中的β受体信号通路。RPP微阵列允许同时测量不同的磷蛋白信号级联。第一个目标是使用RPP微阵列研究新生心肌细胞中β受体信号传导的时间过程。第二个目的是通过使用来自基因敲除小鼠的新生肌细胞来剖析单个β受体亚型的作用。该项目的第三个目标是将这些发现与心力衰竭动物模型的整个心脏研究相关联。

DESCRIPTION (provided by applicant): Heart failure represents a major cause of morbidity and mortality in the United States. The current model of heart failure postulates that neurohumoral activation contributes to the progression of left ventricular dysfunction to clinical heart failure. Chronic beta adrenergic receptor stimulation is believed to contribute to heart failure by causing increased cardiac myocyte apoptosis. Specifically, beta 1 receptors are believed to couple to a pro-apoptotic pathway in myocytes. Recent studies have shown that beta 2 receptor may also couple to an antiapoptotic pathway that promotes myocyte survival. The goal of this project is to analyze beta receptor signaling pathways in cardiac myocytes using a proteomic technology termed reverse phase protein (RPP) lysate microarrays. RPP microarrays allow for the simultaneous measurement of diverse phosphoprotein signaling cascades. The first aim will study a time course of beta receptor signaling in neonatal cardiac myocytes using RPP microarrays. The second aim is to dissect the role of the individual beta receptor subtypes by using neonatal myocytes derived from knockout mice. The third aim of the project is to correlate these findings with studies on whole hearts from an animal model of heart failure.