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. The long-term objective of this project is to define the role that cell-extracellular matrix (ECM) interactions play in the proliferation and differentiation of cardiac muscle cells. Mammalian cardiac myocytes lose their ability to proliferate around the time of birth. Therefore, cardiac myocytes that die after this time are not replaced and the heart subsequently loses cardiac function. The change in their proliferative phenotype during this perinatal period is accompanied by a number of other critical changes in the heart. Among these are sarcomeric development and organization, and content and structure of the ECM. Cell ECM receptors, such as integrins, mediate mechanical and chemical signals from the matrix. In the heart, these signals regulate a number of cellular responses, including proliferation and differentiation. We are currently investigating the molecular mechanisms that cell-ECM interactions use to regulate cell proliferation, focusing on the molecules that regulate the cell cycle. In the initial phase of the project we have determine the effect that different ECM components have on the rate of DNA synthesis of cardiac myocytes. In the next phase of the project we will assay myocyte proliferation and expression of specific cell cycle regulators under conditions where cell-ECM interactions are perturbed. Lastly, we will test the mechanisms defined by the in vitro experiments described above, in vivo by generating transgenic models. In conclusion, cell-ECM interactions play critical roles in the regulation of cellular responses of heart cells. How these interactions impact upon intrinsic regulators of the cell cycle has not been investigated. The intent of this project is to delineate not only the mechanisms of cardiac myocyte proliferation, but also the mechanisms that regulate their development and permanent withdrawal from the cell cycle. This information could be used to perhaps reprogram cardiac myocytes such that therapeutic repair and replacement of lost cardiac myocyte could be accomplished.
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