ROLE OF CMYBP-C IN THE REGULATION OF MYOCARDIUM

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Familial hypertrophic cardiomyopathy (FHC) caused by mutation in the gene encoding cardiac myosin binding protein-C (cMyBP-C) is estimated to affect one in 1,500 Americans. This genetic disorder of the heart is characterized by increased growth in thickness of the left ventricular wall. Despite over 30 years of research, the exact structural location and function of cMyBP-C in muscle cells is far from clear. Our research investigates the structural changes in hearts from genetically-engineered mice which lack cMyBP-C or have cMyBP-C that has been altered to mimic this protein's conformation as it changes in health and disease. We believe cMyBP-C acts to "put the breaks" on the speed of the contracting cycle in heart muscle cells. Using the approach of X-ray diffraction (on the BioCAT beamline, Argonne National Laboratory), we will probe for changes in the molecular structure of heart muscle cells that arise from removing or altering cMyBP-C in our genetically-engineered mice. In support of our hypothesis, we have already found profound effects on the molecular structure in mice lacking this protein. Additionally, altering the conformation of cMyBP-C affects cardiac function, which may be due to changes in its molecular "charge". We will therefore examine structural changes arising from changing the charge on cMyBP-C. Despite advances in biomedicine, the 5-year mortality of heart failure patients remains well above 50%. Thus, understanding the role of cMyBP-C in governing contraction of the heart can lead to development of new treatments such as gene therapy and drugs that control the conformation of cMyBP-C.