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，将纤维化作为尿路功能障碍和下尿路症状(LUTS)的发展和进展的一个促成因素。该团队由密歇根大学两所学院-医学和工程学院-的教职员工组成，这两所学院提供基于实验室的泌尿系疾病研究(Macoska)、治疗前列腺疾病(Hollingsworth)和泌尿生殖系统病理学(KUNJU)以及软组织力学(Arruda)的临床专业知识。该中心团队设计了可行性研究，采用量化方法，旨在测量人类和小鼠组织和细胞中的纤维化变化，并评估这些纤维化变化是否会改变组织硬度/僵硬，从而导致尿路功能障碍。这些研究将检验特定的假设，即通过在老化的前列腺中积累肌成纤维细胞而进行的细胞外基质(ECM)重塑有效地产生纤维化的前列腺组织结构，从而增加组织刚性并降低尿路弹性，从而导致尿流阻塞和下尿路综合征。这些研究分为三个具体目标： 具体目标1将确定老年男性和患有LUTS的男性前列腺周围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性和刚性增加有关。 特异性目标2将在体外阐明老化的前列腺间质分泌的哪些蛋白质有助于肌成纤维细胞分化和细胞外基质功能障碍，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倾向6(SAMP6)和/或KC转基因小鼠是否表现出与纤维化一致的ECM变化，这些变化是否与组织机械刚性和刚性增加有关，这些变化是否影响尿流，以及体内肥胖是否加剧了这种病理。 如果成功，这些研究的结果将打开有效治疗LUTS的新方法的大门，特别是在那些无法耐受或对目前的药物治疗方法无效的男性中。 公共卫生相关性：对数百万老年美国男性来说，下尿路症状(LUT)是一个代价高昂、进展严重的医学问题。目前治疗LUTS的方法主要集中在雄激素消融或平滑肌活动上，但这些方法并不是对所有患者都有效。这项申请旨在确定是否可以开发一种新的针对组织纤维化的疗法来治疗下尿路结石。

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.