Novel Xin Protein in Cardiac Development and Function

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DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the role of a novel cardiac protein, Xin, in development and cardiac function. Xin encodes a proline-rich protein located in adherens junctions of the intercalated discs of adult hearts. Xin antisense oligonucleotide treatment of chick embryos results in disruption of cardiac morphogenesis. Xin protein is co-localized and associated with the N-cadherin/beta-catenin complex suggesting that Xin is a component of adherens junctions of cardiac muscle and may play a vital role in the N-cadherin signaling during cardiac development and function. A mouse knockout to delete the first Xin (mXinalpha) gene has been generated. The knockout mice appear to develop normally. However, further analysis reveals that hearts from adult mXinalpha -/- mice appear to be hypertrophied. Fibrosis and thrombi are occasionally found within the ventricular myocardium of the mXinalpha -/- heart. Furthermore, introduction of pathophysiological stress in a form of pressure-overload to the mXinaalpha -/- mice results in an accelerated rate of hypertrophy. We have also discovered a second mXinbeta gene (mXinbeta, which is upregulated in the mXinalpha knockout hearts. This finding supports the idea that mXinbeta may partially compensate for loss of the mXinalpha gene during development. Our working hypothesis is that mXina and mXina are essential for normal heart development and function and may act by integrating adhesion and signaling. The specific aims are: (1) To further characterize the mXinalpha knockout mice by introducing pathophysiological stress and physiological exercise; (2) To clone and characterize mXinalpha interacting proteins; (3) To clone and characterize the second mXinbeta gene; and (4) To generate and characterize mXinbeta knockout and mXinalpha/mXinbeta double knockout mice. These studies should help provide the basic understanding of mXin protein function in normal cardiac development and function. Only through understanding normal development and cardiac function can intervention strategies be developed to alleviate cardiac defects.