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：
8628080
负责人：
CHAWNSHANG CHANG
金额：
$ 31.1万
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/8628080
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）：已经提出，正常的前列腺发育，良性前列腺增生（BPH）和前列腺癌发育都需要人和啮齿动物中的雄激素/雄激素受体（AR）信号传导。有两种类型的细胞，上皮和基质细胞，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在控制前列腺生长的稳态方面起着重要作用。我们最近的数据表明，双基质 - cre Arko（D-ARKO）小鼠前列腺具有大大降低的基质AR功能，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可以在良性前列腺增生（BPH）和癌变中起差异作用。我们要比较在BPH和癌症中比较基质AR的作用的原因是，这将导致更多见解基础AR如何差异地促进这两种老年男性中这两种最普遍的前列腺疾病的病因和进展。在前列腺领域，即使有体外细胞系或组织重组系统可用来研究正常前列腺发育中的基质AR角色，但肾脏捕获重组系统在免疫缺陷的小鼠中生长，而没有适当的前列腺微环境，并且只能在4-7周内研究。因此，缺乏长期的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。我们建议生成双重CRE-ARKO（D-ARKO），以理解BPH和癌变发展中的基质AR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跨越基质AR在BPH中的作用。 AIM 2。具有基质成纤维细胞/平滑肌选择性双核敲除（D-ARKO）的小鼠模型的生成以及前列腺肿瘤发生和肿瘤进展的研究。 AIM 3。研究基质AR的靶基因和分子机制，这些机制可能会影响BPH和前列腺癌发育过程中上皮。该项目的完成将有助于我们了解基质AR在前列腺稳态中的作用以及癌变的转化和进步，结果还可能导致未来为BPH和前列腺癌开发新的替代疗法。