Role of Dystroglycan in Prostate Function and Regeneration

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Description (provided by applicant): Interactions between epithelial cells and the extracellular matrix are critical for the normal development and maintenance of urologic tissues such as the prostate. Our long term objective is to understand how disruption of these interactions contributes to prostate cancer. We have been focused on the role of dystroglycan, an extracellular matrix receptor expressed on prostate epithelial cells which we have implicated in prostate cancer, as a key mediator of interactions with the extracellular matrix. Using a conditional knockout strategy in the mouse, we have identified a novel role for dystroglycan in regulating cell proliferation in the prostate. Here we propose studies to elucidate the role of dystroglycan in prostate epithelial cell proliferation and how this may be related to the normal function of the prostate, including stem/progenitor cell-mediated renewal of this tissue. Accordingly, we have proposed the following specific aims: 1) Define the role of dystroglycan in tissue organization and function of the mouse prostate. Using age-matched cohorts of dystroglycan-mutant and control mice, we will analyze prostate cellular composition, proliferation and cell death in mice 1-18 months old. Additionally, we will analyze the structure of basement membranes and secretory function in these mice. 2) Analyze the role of dystroglycan in regeneration of the mouse prostate. We will determine whether dystroglycan is required for regeneration of the mouse prostate after androgen withdrawal, co-expressed with markers of prostate stem/progenitor cells and located on cells in the proximal prostatic ducts, a putative stem cell niche. The successful completion of these studies will elucidate a role for dystroglycan in regulating cell proliferation of the prostate epithelium and indicate a role for dystroglycan in prostate stem/progenitor cell function. By understanding for the first time the role(s) that dystroglycan plays in the normal prostate, we can further understand how dystroglycan is involved in the urologic malignancy of prostate cancer. Interactions between epithelial cells and their extracellular matrix environment are critical for proper organization, function and homeostasis of the prostate. Here we will investigate the role of dystroglycan, an extracellular matrix receptor present on prostate epithelial cells, in these processes. This work is relevant to understanding how disruption of the normal biology if the prostate lead to diseases such as prostate cancer.