MI-CURE Research Project

摘要 膀胱功能障碍是最昂贵的下尿路疾病，也是前三大阴性之一 中风和阿尔茨海默病后生活质量的影响因素。尽管进行了数十年的研究，但 感觉膀胱充盈的机制仍不清楚。发展和发展的一个主要障碍 测试膀胱功能障碍的新疗法是我们缺乏对其机制的了解 膀胱充盈是如何被感觉到的。了解这些机制是开发改进的基础 维持和改善膀胱功能的治疗和干预。这个项目的总体目标是 了解压力感应的基础及其与膀胱充盈期间传入神经激活的联系。 我们提出了新的总体概念：(1)局部膀胱壁收缩驱动传入 通过壁张力的变化流出；以及(2)细胞外基质没有足够的硬度，这些 墙体张力不会发生变化。从本质上讲，我们认为这是墙体张力的变化，而不是 短暂的收缩本身--在充盈过程中驱动传入流出。因此，墙的任何变化 顺应性对膀胱充盈感有显著影响。这一概念只专注于 关于膀胱的力学性质，不推测不同细胞类型的作用(S) 参与信号本身。通过首先了解膀胱壁顺应性如何改变感觉，我们可以 然后更深入地研究改变遵从性的机制，从而改进我们的工作 有关膀胱功能障碍的知识。具体目标是：1)确定组成和机械 脱细胞的细胞外基质和完整的膀胱的性质；以及2)阐明 膀胱壁僵硬、膀胱充盈和感觉流出中枢神经系统之间的关系。 为了解决这一重大的知识差距，我们组建了一个跨学科的专家团队 在生理学、细胞生物学、神经病学、统计学和临床泌尿学方面，并招募了一名有前途的新成员 良性泌尿生殖系统疾病的调查员莎拉·罗卡比安卡博士。罗卡比安卡博士有独特的专业知识 在软生物组织的力学表征、微观结构量化和数学 软组织的建模。这个来自博蒙特健康中心和密歇根州立大学的团队， 密歇根泌尿外科跨学科中心位于彼此靠近的地方 研究和教育(MI-CURE)。除了强大的良性泌尿外科研究项目外，还使用 创新和尖端方法，MI-CURE有一个令人兴奋的教育丰富计划，以 培训和指导各级成人学习者，从高中生到医学生，帮助扩大 并加强良性泌尿外科的研究。MI-CURE由老牌的科学家-医生团队共同执导 兰姆博士和总理的关系，并制定了明确的沟通和协调计划。一起， MI-CURE将促进成功的合作、教育倡议和创新研究。

ABSTRACT Bladder dysfunction is the costliest lower urinary tract disorder and one of the top three negative effectors on quality-of-life after stroke and Alzheimer’s Disease. Despite decades of research, the mechanisms by which bladder fullness is sensed are still unknown. A major barrier to developing and testing novel therapies for bladder dysfunction is our lack of understanding the mechanism of how bladder fullness is sensed. Understanding these mechanisms is fundamental to develop improved therpautics and interventions to maintain and improve bladder function. The overall goal of this project is to understand the basis of pressure sensing and its linkage to afferent nerve activation during bladder filling. We propose the novel overarching concept that: (1) localized bladder wall contractions drive afferent outflow through changes in wall tension; and (2) without sufficient stiffness in the extracellular matrix, these changes in wall tension cannot occur. In essence, we propose that it is the changes in wall tension – not the transient contraction itself – that drive afferent outflow during filling. Thus, any change in wall compliance would have significant effects on the sensation of bladder fullness. This concept focuses solely on the mechanical properties of the bladder, without speculation as to the role(s) of different cell types involved in the signaling itself. By first understanding how bladder wall compliance alters sensation, we can then delve deeper into the mechanisms by which compliance is changed, thereby improving our working knowledge of bladder dysfunction. The specific aims are: 1) Determine the composition and mechanical properties of both the decellularized extracellular matrix and the intact urinary bladder; and 2) Elucidate the relationship between bladder wall stiffness, bladder fullness, and sensory outflow to the CNS. To address this significant knowledge gap, we have assembled an interdisciplinary team of experts in physiology, cell biology, neurourology, statistics, and clinical urology and have recruited a promising new investigator to benign genitourinary disease, Dr. Sara Roccabianca. Dr. Roccabianca has unique expertise in soft biological tissue mechanical characterization, microstructural quantification, and mathematical modeling of soft tissues. This assembled team from Beaumont Health and Michigan State University, located in close proximity to each other, form the Michigan Interdisciplinary Center for Urologic Research and Education (MI-CURE). In addition to the strong benign urology research program using innovatice and cutting-edge approaches, MI-CURE has an exciting Educational Enrichment Program to train and mentor all levels of adult learners, from high school students to medical students, to help expand and enhance benign urology research. MI-CURE is co-directed by the established scientist-physician team of Drs. Lamb and Chancellor, with clear communication and coordination plans in place. Together, MI-CURE will foster successful collaborations, education initiaives, and innovative research.