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.
This project investigates disease mechanisms for the development of dilated cardiomyopathy and heart failure. Specifically, the pathological activation of a signaling pathway containing CARP1 and PKCalpha will be characterized using proteome and transcriptome analysis, and tested in animal models for this disease and human samples. Results from this study are expected to refine disease related signaling pathways and may lead to the identification of new therapeutic targets for the DCM and heart failure prevention.
