Molecular Mechanisms of Initiation of Benign Prostatic Hyperplasia

良性前列腺增生发生的分子机制

基本信息

批准号：
9201326
负责人：
Li Xin
金额：
$ 35.66万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9201326
关键词：
Acute Address Adult Age Aging Androgen Receptor Androgens Attenuated Autoimmune Responses Benign Prostatic Hypertrophy Biological Assay Cell Lineage Cells Clinic Clinical Colony-Stimulating Factor Overexpression Combined Modality Therapy Cytokeratin 8 Disease Disease Progression Doxazosin Electron Microscopy Epithelial Epithelial Cell Proliferation Epithelial Cells Etiology Fibrosis Finasteride Goals Histologic Homeostasis Human Immune Immune response Impairment Infiltration Inflammation Inflammatory Interleukin-1 Knowledge Left Life Macrophage Colony-Stimulating Factor Mediating Modeling Molecular Mosaicism Mus Natural regeneration Non-Malignant Pathway interactions Pharmacology Phenotype Prostate Prostatic Proteins Publishing Receptor Signaling Risk Reduction Signal Transduction Specimen Stem cells Stromal Cells Structure Tamoxifen Tight Junctions Tissues Transgenic Mice Urinary Retention Work adrenergic block base clinical risk density genetic approach improved in vivo lower urinary tract symptoms macrophage men mouse model novel overexpression public health relevance receptor expression receptor function targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia is a progressive condition in the aging men characterized by the enlargement of the periurethral regions of prostate gland due to nonmalignant proliferations in both the prostate epithelial and stromal compartments. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. BPH is often accompanied by lower urinary tract symptoms (LUTS). BPH is rarely fatal, but may cause serious life-threatening complications such as acute urinary retention if left untreated. Androgen targeted therapies such as finasteride are clinically employed for the treatment of BPH. However, the MTOPS study shows that even combination therapy using finasteride and doxazosin only leads to a 66% reduction of risk for clinical progression of LUTS/BPH, suggesting the existence of unrecognized mechanisms that promote disease progression. The goal of this application is to investigate novel molecular mechanisms that contribute to BPH initiation and progression. This application is based on our novel preliminary observation that attenuating the androgen receptor signaling in prostate epithelial cells induces an inflammatory microenvironment. We hypothesize that this prostatic inflammatory microenvironment contributes to progression of BPH. Through the three Aims in this application, we seek to generate novel mouse models for human BPH, use mouse models to determine the contribution of immune cells to prostate epithelial cell proliferation, and identiy novel key signaling mediated by the inflammatory prostatic microenvironment that is capable of promoting epithelial cell proliferation.

描述（由申请人提供）：良性前列腺增生是老年男性的一种进行性疾病，其特征是前列腺尿道周围区域由于前列腺上皮和间质区的非恶性增殖而增大。估计50%的男性患有组织学疾病。 50 岁出现 BPH 的证据，以及 80 岁出现 BPH 的 75% 常伴有下尿路症状。 (LUTS)。 BPH 很少致命，但如果不及时治疗，可能会导致严重的危及生命的并发症，例如非那雄胺等雄激素靶向疗法，但 MTOPS 研究表明，即使是联合治疗。使用非那雄胺和多沙唑嗪的治疗仅使 LUTS/BPH 临床进展的风险降低 66%，这表明存在促进疾病进展的未被识别的机制。该应用的目的是研究有助于 BPH 发生和进展的新分子机制。该应用基于我们新的初步观察，即减弱前列腺上皮细胞中的雄激素受体信号传导会诱导炎症微环境。通过本申请的三个目标，我们寻求为人类 BPH 生成新的小鼠模型，使用小鼠模型确定免疫细胞对前列腺上皮细胞增殖的贡献，并识别新的关键信号传导。由能够促进上皮细胞增殖的炎症性前列腺微环境介导。