Role of Prostatic Fibrosis in BPH/LUTS Development & Symptomology

描述（由申请人提供）：拟议的规划中心汇集了一个多学科团队，以探索一种新的范式，将纤维化作为泌尿功能障碍和下尿路症状（LUTS）发展和进展的促成因素。该团队由来自密歇根大学医学和工程两所学校的教师组成，提供泌尿系统疾病（Macoska）实验室研究的广泛专业知识，治疗前列腺疾病（Hollingsworth）和泌尿生殖病理学（Kunju）的临床专业知识，以及软组织力学（Arruda）。该中心团队设计了可行性研究，采用定量方法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/刚度，从而导致泌尿功能障碍。这些研究将测试特定的假设，即细胞外基质（ECM）通过在老化的前列腺中积累肌成纤维细胞进行重塑，有效地产生纤维化的前列腺组织结构，增加组织硬度并降低尿道灵活性，导致尿流阻塞和LUTS。这些研究分为三个具体目标： 具体目标1将确定来自老年男性和特别是患有LUTS的人前列腺的尿道周围区域的组织是否表现出与纤维化一致的细胞外基质（ECM）的变化，以及这些变化是否与组织的机械刚度和硬度增加相关。 具体目标2将阐明老化前列腺基质分泌的蛋白质有助于体外肌成纤维细胞分化和ECM功能障碍，并测试抑制或逆转这些变化的治疗方法。 具体目标3将确定衰老加速小鼠俯卧6（SAMP 6）和/或KC转基因小鼠是否表现出与纤维化一致的ECM变化，这些变化是否与增加的组织机械刚度和硬度相关，这些变化是否影响尿流，以及这种病理是否因体内肥胖而加剧。 如果成功，这些研究的结果将为有效治疗LUTS的新方法打开大门，特别是在无法耐受或无法对当前医学治疗方法做出反应的男性中。 公共卫生相关性：下尿路症状（LUTS）是数百万美国老年男性的一个昂贵且严重的渐进性医学问题。目前治疗LUTS的方法主要集中在雄激素或平滑肌活性的消融，但这些并不是对所有患者都有效。本申请寻求确定是否可以开发靶向组织纤维化的新类别的治疗剂来治疗LUTS。

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.