Pulmonary Myofibroblast Growth and Proliferation

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DESCRIPTION (provided by applicant): Myofibroblasts are unique cells possessing ultrastructural characteristics of both muscle an non-muscle cells. Under normal conditions, myofibroblasts are essential for the formation of functional adult tissues and are intimately involved in tissue homeostasis and wound healing. Activation of myofibroblasts is characterized by an increase in alpha smooth muscle actin expression, proliferation and contractility. It is their persistence during injury, however, that has implicated them in many disease states including fibrosis. We have found that these cells also express multiple structural and regulatory skeletal muscle proteins, including MyoD, in response to cytokine treatment. Despite the expression of MyoD, an inhibitor of the cell-cycle, myofibroblasts do not terminaly differentiate. Because lymphangioleiomyomatosis (LAM) cells and myofibroblasts share many cellular phenotypes, we propose that myofibroblasts contribute to the pathogenesis of LAM. Therefore, the goal of this fellowship is to determine the cellular and molecular phenotypes of pulmonary myofibroblasts and subsequently, to elucidate the intracellular mechanisms responsible for growth and proliferation in normal and diseased lung. This project has three related aims directed at this goal. (1) The molecular and cellular characteristics of isolated pulmonary myofibroblasts will be determined in order to establish a basis for evaluating changes that occur in these cells in response to injury. (2) The phenotypic cellular and molecular changes that occur in myofibroblasts as a result of the induction of pulmonary fibrosis will be determined. This information will be invaluable in elucidating the relationship between myofibroblast activation and disease. (3) Finally, once we have fully characterized myofibroblasts in normal and diseased lung we will begin to elucidate the molecular mechanisms responsible for their proliferation. Ultimately these studies will provide the foundation for future investigations in human LAM tissue and will be critical in establishing the link between LAM cell proliferation and the development of new therapeutics.