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Estrogens stimulate prostatic collagen synthesis to drive fibrosis and LUTD

雌激素刺激前列腺胶原蛋白合成，促进纤维化和 LUTD

基本信息

批准号：
10700924
负责人：
WILLIAM A RICKE
金额：
$ 25.44万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-24 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10700924
关键词：
5 Alpha-Reductase Inhibitor Address Adrenergic alpha-Antagonists Affect Anatomy Benign Benign Prostatic Hypertrophy Biological Bladder CRISPR/Cas technology Caring Cell physiology Cells Clinic Clinical Clinical Treatment Collaborations Collagen Communities Contrast Media Data Databases Deposition Development Disease Disease Progression Epithelial Cells Estrogen Receptor alpha Estrogen Receptors Estrogens Etiology Event Extracellular Matrix Fibroblasts Fibrosis Foundations Functional disorder Funding Opportunities Genetic Transcription Goals Health Care Costs Healthcare Hormone Receptor Hyperplasia Image Imaging Techniques In Vitro Instruction Lead Link Lower urinary tract Magnetic Resonance Imaging Mediator Medical Medicine Methods Modeling Molecular Molecular Mechanisms of Action Monitor Mus Obstruction Outcome Pathway interactions Physiological Pre-Clinical Model Preclinical Testing Prevention Prostate Prostatic Prostatic hypertrophy Protocols documentation Publishing Quality of life Receptor Signaling Reproducibility Research Research Project Grants Resources Signal Transduction Smooth Muscle Smooth Muscle Myocytes Specimen Stratification Stromal Cells Techniques Testing Tissues Translating Treatment Efficacy Urethra Urinary tract Urology antifibrotic treatment cell type clinical translation clinically relevant clinically significant cost effective therapy efficacy evaluation experimental study gain of function human disease in vivo lower urinary tract symptoms men mortality risk mouse model new therapeutic target novel outreach patient population patient stratification permissiveness response spectrograph targeted treatment therapeutic target urinary web site

项目摘要

PROJECT SUMMARY Healthcare costs for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hyperplasia (BPH) are in the billions of dollars annually. Therapies for BPH/LUTS target smooth muscle contractility with α-blockers or hyperplasia with 5α-reductase inhibitors. Although these therapies can be medicinal, they are not effective/durable for all; this leaves millions of men in the US needing more effective therapies. The standard of medical care for BPH/LUTS currently over-treats this patient population, in part due to a poor understanding of etiology and progression. There is an apparent need to define what BPH represents in patient populations as well as to identify the true anatomic, cellular, and molecular causes of the disease. This may elucidate the true causes in development and progression of the disease as well as institute effective therapies. The overarching goal of the O’Brien Center for Benign Urology Research is to identify the mechanisms that result in lower urinary tract dysfunction and prostate-related LUTS. Previous studies have demonstrated prostatic collagen deposition coincident with prostate stiffness, LUTS, and failed medical treatment supporting the concept that BPH/LUTS is, in part, a fibrotic disease. However, this brings up a translational challenge because treatment of prostatic fibrosis cannot occur until cellular and molecular pathways have been identified. As such, the goal is to identify the anatomical, cellular, and molecular origins of prostate fibrosis in men with BPH/LUTS. Recently, estrogens, specifically signaling through estrogen receptor (ER)α, was discovered to be necessary for the development of prostatic fibrosis and LUTD in mice. Although, multiple stromal and epithelial cells express ERα, a subpopulation of ERα positive prostatic fibroblasts and/or smooth muscle cells could be responsible for increased collagen deposition. These cells are sensitive to estrogens and produce large amounts of collagen in vitro and in vivo. Aim 1 will address the ER molecular mechanism of action in the transcription of Col1a1 by determining if classical or non-classical ER signaling is necessary. Next, collagen accumulation has been linked with BPH/LUTS, but it is uncertain if collagen/fibrosis acts independently or in collaboration with prostate hyperplasia; Aim 2 will test the hypothesis that gain of collagen function promotes LUTD independent of prostate hyperplasia. Clinical translation of our findings is a goal of the center; Aim 3 will test the hypothesis that clinically relevant antifibrotics are effective in the treatment of prostatic fibrosis. Lastly, stratification of men with fibrotic prostates is imperative to increase treatment efficacy. To address this challenge, advanced and novel collagen MR imaging techniques will be used to assess whether prostatic fibrosis can be identified in preclinical models. By establishing cellular and molecular mechanistic connections between fibrosis and BPH/LUTS as well as preclinical testing and patient stratification our collaborative and synergistic research, Project 1 will lay the groundwork for impactful discoveries that elucidate an important etiology of BPH/LUTS and may ultimately translate into the clinic.

项目总结