Integrated crosstalk of thin filament post-translational modifications

描述（申请人提供）：由心脏收缩功能障碍引起的心脏病是当今美国人的头号杀手。调节心脏收缩的蛋白受到激酶磷酸化和磷酸酶去磷酸化的严格翻译后修饰（PTM）调控。肌钙蛋白（Tn）蛋白复合物是心肌收缩调节的核心。在对心脏应激的反应中，Tn复合体受到许多ptm的影响。磷酸化是肌PTM的主要机制，其紧密平衡对正常心脏功能至关重要。其他非磷酸化的Tn PTMs也会发生。迄今为止，大多数Tn蛋白PTMs都是作为孤立事件来研究的，然而，多个Tn PTMs的联合功能不能从孤立事件的功能来确定。本研究将主要肌钙蛋白收缩调节磷酸化和其他新型PTM事件作为联合事件进行研究，以更好地了解Tn PTM在心脏发生时的生理调节功能。为此，我们将采用肌钙蛋白模型和含有单个或多个PTMs的转基因动物模型来评估生化和动物水平的功能。这些研究的目的是对调节心脏功能的事件进行更深入的生理理解，以确定治疗心功能障碍的新药物靶点。

DESCRIPTION (provided by applicant): Heart disease resulting from cardiac contractile dysfunction is the number one killer of people in the US today. The proteins that regulate cardiac contractile are under the tight post-translational modification (PTM) regulation of kinase phosphorylation and phosphatase de-phosphorylation. Central to the regulation of cardiac muscle contraction is the troponin (Tn) protein complex. In response to cardiac stress the Tn complex is subjected to a number of PTMs. Phosphorylation represents the primary mechanism of muscle PTM and it's tight balance is critical to normal heart function. Other non-phosphorylation Tn PTMs also occur. To date most Tn protein PTMs have been studied as isolated events, however the combined function of multiple Tn PTMs cannot be determined from function of the isolated events. This proposal investigates the primary troponin contractile regulation phosphorylation and other novel PTM events as combined events to better understand the physiological regulatory function of Tn PTMs as they occur in the heart. To this end, we will employ model troponin proteins and transgenic animal models containing single or multiple PTMs to evaluate biochemical and animal level function. The goal of these studies is to develop a more physiological understanding of the events that regulate heart function in order to identify novel drug targets to treat cardiac dysfunction.