Project 2: Molecular and Functional Crosstalk of Progesterone Receptor

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Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women. The overall incidenced of leiomyomas may be as high as 70-75% while the rate of symptomatic leiomyomas in women ranges from 25-60%. However, available treatments for leiomyomas are limited due in large part to the fact that the mechanisms regulating the development and growth of these tumors are still not well understood. Two essential features of leiomyoma tumors are an increase in smooth muscle cell proliferation and excessive extracellular matrix (ECM) deposition. Thus leiomyomas display characteristics similar to other fibrotic diseases such as keloids and renal fibrosis. Changes in production of ECM proteins, particularly collagen, cause profound changes in proliferation and differentiation of smooth muscle cells or fibroblast cells. Recent studies have shown that collagen can act in concert with various growth factors to regulate proliferation of these cells. We hypothesize that the increased proliferation exhibited by leiomyoma cells is due to a major shift in the ECM environment caused by increased synthesis of new, monomeric collagen by these cells. We also hypothesize the antifibrotic drugs that inhibit collagen production may be effective treatments for leiomyomas. The specific aims of this proposal are: 1) To determine whether changes in collagen production by leiomyoma SMCs regulate proliferation by altering interactions between growth factor receptors and integrins. Our goal is to determine whether the antiproliferative effect of antifibrotic drugs is dependent on a decrease in newly synthesized collagen and whether this alters tyrosine kinase receptor signaling; 2) To determine whether alterations in collagen production by leiomyoma SMCs regulate progression of these cells through the cell cycle and induce apoptosis by blocking the AKT signaling pathway. This will be addressed using siRNA and adenoviral infection approaches to block components of the AICT signaling pathway; 3) To determinen the efficacy of the antifibrotic drug halofuginone as a treatment for leiomyomas in an in vivo animal model for leiomyomas, the Eker rat. RELEVANCE (See instmctions): The results of the proposed studies will provide new insights into how changes in the extracellular matrix environment contribute to the growth of leiomyomas through regulation of cell proliferation or cell death. Most importantly, these studies will have significant clinical relevance as they may lead to the identification of a new group of drugs as potential therapeutic agents for treatment of leiomyomas.