Stromal AR Roles in Prostate Hyperplasia and Cancer

描述(申请人提供)：已经提出，在人类和啮齿动物中，正常的前列腺发育、良性前列腺增生(BPH)和前列腺癌的发展都需要雄激素/雄激素受体(AR)信号。有两种类型的细胞，即上皮细胞和间质细胞，它们构成了前列腺的结构，并调节了其生理功能。AR在上皮细胞和间质细胞中的表达可能在控制前列腺生长的动态平衡中起重要作用。我们最近的数据表明，双间质ARKO(d-ARKO)小鼠的前列腺间质AR功能显著降低，并对前列腺上皮细胞的动态平衡产生影响。我们推测，间质细胞中的AR可能在良性前列腺增生症(BPH)和癌变中发挥不同的作用。我们之所以想比较间质AR在前列腺增生症和癌症中的作用，是因为它将导致更多的洞察，间质AR如何在这两种最常见的老年人前列腺疾病的病因和进展中起到不同的作用。在前列腺领域，虽然已有体外细胞系或组织重组系统来研究基质AR在正常前列腺发育中的作用，但肾俘获重组系统是在缺乏适当的前列腺微环境的免疫缺陷小鼠中生长的，只能在4-7周内进行研究。因此，目前还缺乏长期的体内模型来研究间质AR对BPH和前列腺癌发生的影响。到目前为止，还没有合适的临床前小鼠模型来研究间质AR的功能。我们建议产生双cre-Arko(d-Arko)，以了解间质AR在BPH发生和癌变中的作用。将追求三个具体目标。目的1.通过间质d-Arko小鼠与催乳素转基因小鼠杂交，研究间质AR在BPH中的作用。目的2.建立小鼠间质成纤维细胞/平滑肌选择性双中心AR基因敲除(d-ARKO)模型，研究其在前列腺癌发生发展中的作用。目的3.研究间质AR在前列腺增生症和前列腺癌发生发展过程中影响上皮细胞的靶基因及其分子机制。该项目的完成将有助于我们深入了解间质AR在前列腺动态平衡和癌症转化和进展中的作用，结果还可能导致开发未来治疗BPH和前列腺癌的新方法。

DESCRIPTION (provided by applicant): It has been suggested that normal prostate development, benign prostate hyperplasia (BPH), and prostate cancer development all require androgen/androgen receptor (AR) signaling in human and rodent. There are two types of cells, epithelial and stromal cells, constituting the prostate gland structure and mediating the physiological functions. The expression of AR in both epithelial and stromal cells may play important roles in controlling the homeostasis of prostate growth. Our recent data suggested that double stromal-cre ARKO (d-ARKO) mouse prostates have a profoundly reduced stromal AR function and impact on the homeostasis of prostate epithelial cells. We hypothesize that the AR in the stromal cells could play differential roles in benign prostate hyperplasia (BPH) and carcinogenesis. The reason we would like to compare stromal AR role in the BPH vs. cancer is that it will lead to more insights how stromal AR may differentially contribute to the etiology and progression of these two most commen prostate diseases in elder men. In the prostate field, even though there are available in vitro cell lines or tissue recombinant system to study stromal AR roles in normal prostate development, the kidney capture recombination system is grown in immune deficient mice without proper prostate microenvironment and can be only studied in 4-7 weeks. Therefore there is a lack of long-term in vivo model to investigate stromal AR impact on the BPH and prostate carcinogenesis. To date, there are still no suitable preclinical mouse models to study the stromal AR function. We propose to generate the double cre-ARKO (d-ARKO) for understanding the stromal AR role in development of BPH and carcinogenesis. Three Specific Aims will be pursued. Aim 1. To study the stromal AR role in BPH by crossing stromal d-ARKO mice with prolactin transgenic mice. Aim 2. Generation of mouse models with stromal-fibroblast/smooth muscle selective double-cre AR knockout (d-ARKO) and investigation of prostate tumorigenesis and tumor progression. Aim 3. Studying target gene and molecular mechanisms of stromal AR that could affect the epithelium during development of BPH and the prostate cancer. The accomplishment of the project will help us gain insights on the role of stromal AR in the prostate homeostasis and cancerous transformation and progression, and the results could also lead to developing new alternative treatments for BPH and prostate cancer in the future.