Signaling Pathways in Dilated Cardiomyopathy

 描述（由申请人提供）：许多研究致力于描述导致扩张型心肌病（DCM）发展并最终导致心力衰竭的心脏信号通路。动物模型，如发生DCM的MLP/Csrp3敲除已被用于描绘和鉴定DCM发生中涉及的特定途径和途径组分。已知的途径组分包括蛋白激酶Calpha、参与肾上腺素能受体信号传导的蛋白质和受磷蛋白。任何这些组分的基因消除和/或小分子抑制导致在MLP敲除中预防DCM。尽管这些研究和动物模型提供了一些见解，但关于这些看似不相关的通路组分是如何联系的，以及尚未鉴定的组分是否可能在DCM发展中发挥类似作用的信息有限。我们发现，MLP基因敲除小鼠与心脏锚蛋白重复蛋白（CARP1/Ankrd1）基因敲除小鼠杂交时，不会发生DCM。初步研究产生了这样的假设，即含有CARP1和PKCalpha的心脏信号传导途径的病理激活导致MLP敲除小鼠中DCM的发展。我们进一步认为，PKCalpha的心脏底物的异常翻译后修饰可能参与了这种疾病的发展。因此，拟议的5年项目的总体目标是研究和表征PKCalpha病理修饰的蛋白质底物，并确定CARP1功能对心脏基因程序的病理调节和扩张型心肌病的发展。我们的目标是实现这些目标，通过研究的变化，磷酸化蛋白质组使用蛋白质组学方法。具体而言，将分析在MLP小鼠中观察到的PKCalpha异常激酶活性引起的蛋白质翻译后变化。鉴定的PKCalpha底物的进一步表征将描述疾病相关变化及其对疾病病因学的生物学作用。此外，我们正在研究的作用CARP1的病理调制的心脏基因程序在MLP动物的转录组分析。我们将进一步描述CARP1和PKCalpha是否在MLP敲除小鼠模型以外的DCM发展中以及心力衰竭患者中发挥作用。初步研究表明，该项目的结果将进一步控制DCM发展中涉及的信号通路，并可能导致确定疾病预防的新治疗靶点。

 DESCRIPTION (provided by applicant): Much research has been devoted to delineate cardiac signaling pathways that lead to the development of dilated cardiomyopathy (DCM) and ultimately heart failure. Animal models, like the MLP/Csrp3 knockout that develops DCM have been used to delineate and identify specific pathways and pathway components involved in DCM development. Known pathway components include protein kinase Calpha, proteins involved in adrenergic receptor signaling, and phospholamban. Genetic ablation and/or small molecule inhibition of any of these components results in the prevention of DCM in MLP knockouts. Despite the insight that these studies and animal models provided, there is limited information of how these seemingly unconnected pathway components are linked, and whether as of yet unidentified components might play similar roles for DCM development. We found that MLP knockout mice when crossbred with the cardiac ankyrin repeat protein (CARP1/Ankrd1) knockout mice do not develop DCM. Preliminary investigations resulted in the hypothesis that pathological activation of a cardiac signaling pathway containing CARP1 and PKCalpha leads to the development of DCM in MLP knockout mice. We argue further that aberrant posttranslational modification of cardiac substrates for PKCalpha may be involved in the development of this disease. The overall goal of the proposed 5 year project is therefore to investigate and characterize protein substrates that are pathologically modified by PKCalpha, and identify CARP1 functions for the pathological modulation of the cardiac gene program and development of dilated cardiomyopathy. We aim to achieve these goals by investigating changes to the phospho-proteome using a proteomics approach. Specifically, posttranslational changes to proteins caused by aberrant kinase activity of PKCalpha observed in MLP mice will be analyzed. Further characterization of identified PKCalpha substrates will delineate disease relevant changes and their biological roles for the disease etiology. In addition, we are investigating the role of CARP1 for the pathological modulation of the cardiac gene program in MLP animals by a transcriptome analysis. We will further delineate whether CARP1 and PKCalpha play roles in DCM development beyond the MLP knockout mouse model, and in heart failure patients. Preliminary studies indicate that results from this project will further reine signaling pathways involved in DCM development and may lead to the identification of new therapeutic targets for the disease prevention.