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（由适用提供）：良性前列腺增生是在衰老的男性中的一种渐进状态，其特征是前列腺上皮和基质隔室中前列腺腺周围区域的扩张。估计有50％的男性在50岁时具有BPH的组织学证据，到80岁的男性有75％。 BPH通常伴随着较低的尿路符号（LUTS）。 BPH很少致命，但可能会导致严重威胁生命的并发症，例如如果未经治疗，急性尿位率。雄激素靶向疗法（如非那雄胺）在临床上用于BPH的治疗。然而，MTOPS研究表明，即使使用非那雄胺和毒素的联合疗法也仅导致LUTS/BPH临床进展的风险降低66％，这表明存在未认识到促进疾病进展的未识别机制。该应用的目的是研究有助于BPH启动和进展的新型分子机制。该应用是基于我们新颖的初步观察结果，该观察会减弱前列腺上皮细胞中雄激素受体信号传导诱导炎症微环境。我们假设这种前列腺炎症微环境有助于BPH的发展。通过此应用中的三个目标，我们试图为人类BPH生成新型的小鼠模型，使用小鼠模型来确定免疫细胞对前列腺上皮细胞增殖的贡献，并确定能够促进上皮细胞增殖的炎性前列腺微环境介导的新型关键信号传导。