Role of Prostatic Fibrosis in BPH/LUTS Development & Symptomology

描述（由申请人提供）：拟建的规划中心汇集了一个多学科团队，探索将纤维化作为泌尿功能障碍和下尿路症状（LUTS）发展和进展的促进因素的新范式。该团队由密歇根大学医学院和工程系两所学院的教师组成，他们在泌尿系统疾病（Macoska）的实验室研究、前列腺疾病（Hollingsworth）和泌尿生殖系统病理学（Kunju）的临床研究以及软组织力学（Arruda）方面提供广泛的专业知识。该中心团队设计了可行性研究，采用定量方法来测量人类和小鼠组织和细胞的纤维化变化，并评估这些纤维化变化是否会改变组织硬度/僵硬度，从而导致尿功能障碍。这些研究将验证细胞外基质（ECM）重构通过积累肌成纤维细胞在老化的前列腺有效地产生纤维化的前列腺组织结构，增加组织刚性和降低尿道灵活性，导致尿流阻塞和LUTS的具体假设。这些研究分为三个具体目标：

DESCRIPTION (provided by applicant): The proposed planning Center brings together a multidisciplinary team to explore a new paradigm that incorporates fibrosis as a contributing factor to urinary dysfunction and lower urinary tract symptoms (LUTS) development and progression. This team comprises faculty from two schools within the University of Michigan - Medicine and Engineering - that provides broad expertise in laboratory-based studies of urologic disease (Macoska), clinical expertise in treating prostate disease (Hollingsworth) and genitourinary pathology (Kunju), and in soft tissue mechanics (Arruda). The Center team has designed feasibility studies that employ quantitative approaches designed to measure fibrotic changes in human and mouse tissues and cells and to assess whether these fibrotic changes alter tissue rigidity/stiffness and thereby contribute to urinary dysfunction. These studies will test the specific hypothesis that extracellular matrix (ECM) remodeling by accumulating myofibroblasts in the aging prostate effectively generates a fibrotic prostate tissue architecture that increases tissue rigidity and reduces urethral flexibility, resulting in urinary flow obstruction and LUTS. These studies are organized into three Specific Aims: Specific Aim 1 will determine whether tissues from the peri-urethral area of the human prostate in aging men and particularity those with LUTS demonstrate changes in the extracellular matrix (ECM) consistent with fibrosis, and whether these changes are associated with increased tissue ' mechanical rigidity and stiffness. Specific Aim 2 will elucidate which proteins secreted by aging prostate stroma contribute to myofibroblast differentiation and ECM dysfunction in vitro, and test therapeutic approaches to inhibit or reverse these changes. Specific Aim 3 will determine whether Senescence-Accelerated Mouse Prone 6 (SAMP6) and/or KC Transgenic mice exhibit changes in the ECM consistent with fibrosis, whether these changes are associated with increased tissue mechanical rigidity and stiffness, whether these changes affect urinary flow, and whether this pathology is exacerbated by obesity in vivo. If successful, the results of these studies will open the door to a new approach to effectively treat LUTS especially among men who cannot tolerate or fail to respond to current medical therapeutic approaches. PUBLIC HEALTH RELEVANCE: Lower urinary tract symptoms (LUTS) are a costly and critically progressive medical problem for millions of aging American men. Current therapeutic approaches for LUTS are focused on the ablation of androgen or smooth muscle activity, but these are not effective for all patients. This application seeks to determine whether a new class of therapeutics targeting tissue fibrosis may be developed to treat LUTS.