Role of Dystroglycan in Prostate Function and Regeneration

描述（由申请人提供）：上皮细胞和细胞外基质之间的相互作用对泌尿系统组织（如前列腺）的正常发育和维持至关重要。我们的长期目标是了解这些相互作用的破坏是如何导致前列腺癌的。我们一直专注于糖酐的作用，糖酐是一种在前列腺上皮细胞上表达的细胞外基质受体，我们认为它与前列腺癌有关，是与细胞外基质相互作用的关键媒介。在小鼠中使用条件敲除策略，我们已经确定了糖酐在调节前列腺细胞增殖中的新作用。在这里，我们提出了一些研究来阐明歧义糖聚糖在前列腺上皮细胞增殖中的作用，以及它如何与前列腺的正常功能相关，包括干细胞/祖细胞介导的前列腺组织更新。因此，我们提出了以下具体目标：1)明确歧义糖聚糖在小鼠前列腺组织和功能中的作用。使用年龄匹配的糖酐异常突变小鼠和对照小鼠，我们将分析1-18个月大小鼠的前列腺细胞组成、增殖和细胞死亡。此外，我们将分析这些小鼠的基底膜结构和分泌功能。2)分析糖酐在小鼠前列腺再生中的作用。我们将确定雄性激素停用后小鼠前列腺再生是否需要三磷酸甘聚糖，它与前列腺干细胞/祖细胞标记物共表达，位于近端前列腺导管（一个假定的干细胞生态位）的细胞上。这些研究的成功完成将阐明糖歧义在调节前列腺上皮细胞增殖中的作用，并表明糖歧义在前列腺干细胞/祖细胞功能中的作用。通过首次了解糖异常蛋白在正常前列腺中的作用，我们可以进一步了解糖异常蛋白是如何参与前列腺癌泌尿系统恶性肿瘤的。上皮细胞与其细胞外基质环境之间的相互作用对前列腺的正常组织、功能和稳态至关重要。在这里，我们将研究三聚糖酐的作用，一种存在于前列腺上皮细胞上的细胞外基质受体，在这些过程中。这项工作与了解前列腺正常生物学的破坏如何导致前列腺癌等疾病有关。

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.