Stromal AR Roles in Prostate Hyperplasia and Cancer

基质 AR 在前列腺增生和癌症中的作用

基本信息

批准号：
8459341
负责人：
CHAWNSHANG CHANG
金额：
$ 30.14万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459341
关键词：
Address Affect Aging Androgen Receptor Androgens Animal Model Animals Apoptosis Area Attention Benign Prostatic Hypertrophy Biological Assay Biological Models Breeding Cancer Etiology Cancerous Cell Culture Techniques Cell Line Cell physiology Cells Cessation of life ChIP-seq Choristoma Coculture Techniques Data Development Disease Disease Progression Elderly Elderly man Endocrine system Epithelial Epithelial Cells Epithelium Etiology Fibroblasts Frequencies Future Gene Targeting Generations Genetic Recombination Growth Homeostasis Human Image Immune In Vitro Incidence Investigation Knock-out Knockout Mice Lead Lesion by Stage Malignant Neoplasms Malignant neoplasm of prostate Mediating Mesenchymal Modeling Molecular Mus PTEN gene Pathway interactions Phenotype Physiological Play Prolactin Prostate Prostatic Diseases Prostatic Neoplasms Prostatic hypertrophy Publications Rattus Receptor Signaling Recombinants Reporting Research Rodent Role SCID Mice Signal Transduction Smooth Muscle Stream Stromal Cells Structure Symptoms System Therapeutic Tissues Transgenic Mice Urination alternative treatment cancer initiation carcinogenesis cell stroma cell type implantation in vivo in vivo Model insight intraepithelial men mouse model nephrogenesis novel pre-clinical probasin promoter prostate cancer cell prostate cancer model prostate carcinogenesis public health relevance receptor function response tumor progression urinary

项目摘要

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.

描述（由申请人提供）：已经表明，人类和啮齿类动物的正常前列腺发育、良性前列腺增生（BPH）和前列腺癌发展都需要雄激素/雄激素受体（AR）信号传导。有两种类型的细胞，即上皮细胞和基质细胞，构成前列腺结构并介导生理功能。 AR 在上皮细胞和基质细胞中的表达可能在控制前列腺生长的稳态中发挥重要作用。我们最近的数据表明，双基质-cre ARKO (d-ARKO) 小鼠前列腺的基质 AR 功能大大降低，并对前列腺上皮细胞的稳态产生影响。我们假设基质细胞中的 AR 可能在良性前列腺增生 (BPH) 和癌变中发挥不同的作用。我们想要比较间质 AR 在 BPH 与癌症中的作用的原因是，这将带来更多的见解，即间质 AR 如何对老年男性中这两种最常见的前列腺疾病的病因和进展产生不同的影响。在前列腺领域，尽管有可用的体外细胞系或组织重组系统来研究间质AR在正常前列腺发育中的作用，但肾捕获重组系统是在没有适当前列腺微环境的免疫缺陷小鼠中生长的，并且只能在4年中进行研究-7周。因此，缺乏长期体内模型来研究基质 AR 对 BPH 和前列腺癌发生的影响。迄今为止，仍然没有合适的临床前小鼠模型来研究基质AR功能。我们建议生成双 cre-ARKO (d-ARKO)，以了解基质 AR 在 BPH 发展和癌变中的作用。将追求三个具体目标。目的 1. 通过将基质 d-ARKO 小鼠与催乳素转基因小鼠杂交，研究基质 AR 在 BPH 中的作用。目标 2. 生成基质成纤维细胞/平滑肌选择性双 cre AR 敲除 (d-ARKO) 小鼠模型并研究前列腺肿瘤发生和肿瘤进展。目的3.研究BPH和前列腺癌发生过程中基质AR影响上皮的靶基因和分子机制。该项目的完成将帮助我们深入了解基质AR在前列腺稳态和癌变和进展中的作用，并且结果还可能导致未来开发针对BPH和前列腺癌的新替代疗法。