Integrated crosstalk of thin filament post-translational modifications

描述（由申请人提供）：心脏收缩功能障碍导致的心脏病是当今美国人的头号杀手。调节心脏收缩的蛋白质处于激酶磷酸化和磷酸酶去磷酸化的严格翻译后修饰（PTM）调节下。调节心肌收缩的中心是肌钙蛋白（Tn）蛋白复合物。在响应心脏应激时，Tn复合物经受许多PTM。磷酸化代表了肌肉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Tn PTM也会发生。迄今为止，大多数Tn蛋白PTM已被研究为孤立的事件，然而，多个Tn PTM的组合功能不能从孤立的事件的功能确定。本提案将主要肌钙蛋白收缩调节磷酸化和其他新型PTM事件作为组合事件进行研究，以更好地了解Tn PTM在心脏中发生时的生理调节功能。为此，我们将采用模型肌钙蛋白蛋白和含有单个或多个PTM的转基因动物模型来评估生物化学和动物水平的功能。这些研究的目的是发展对调节心脏功能的事件的更多生理学理解，以确定治疗心功能不全的新药物靶点。

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.