The aim of this five-year proposal is to test the hypothesis that Cypher is a critical linker protein, which serves to mediate structural integrity and signaling pathways at the Z-line via its interactions with a-actinin 2, PKC, PKA, and potentially other Z-line proteins. Each Cypher isoform has distinct role and the D626N mutation of Cypher results in dilated cardiomyopathy (DCM) through increased affinity of Cypher for PKC. The overall goals of this proposal are to understand the role of Cypher and its isoforms in cardiac function and to gain insight into the mechanisms by which the mutation D626N causes DCM. We will achieve these goals by comprehensive histological, biochemical, and physiological analyses of the cardiac phenotypes of several existing genetically manipulated mouse lines as well as mouse lines in the process of being made. Accordingly, the Specific Aims are: 1. To understand the functional role of Cypher in heart. We will investigate the function of Cypher in heart by analyzing two mouse lines in which Cypher is selectively ablated in developing or adult heart. 2. To determine the biological function of long and short Cypher splice isoforms, Cypher1 and Cypher2, respectively. We will investigate the function of long and short Cypher isoforms by analyzing in detail two mouse lines in which each isoform is selectively ablated. 3. To understand the role of Cypher's interaction with PKC in DCM. The proposed studies will help us to understand the biological function of Cypher and its isoforms at molecular, cellular, and physiological levels. Furthermore, we will gain insight into the mechanisms by which mutations in Cypher causes DCM, thereby improving our general understanding of DCM. In addition, the mouse lines will be useful as test models for potential therapies. ? ? ?
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