MI-CURE Research Project

摘要 膀胱功能障碍是最昂贵的下尿路疾病和前三名的负面影响之一， 中风和阿尔茨海默病后生活质量的影响因素。尽管经过几十年的研究， 感知膀胱充盈的机制仍然未知。发展的主要障碍， 测试膀胱功能障碍的新疗法是我们缺乏了解的机制， 如何感知膀胱充盈。了解这些机制对于开发改进的 治疗和干预，以维持和改善膀胱功能。该项目的总体目标是 了解压力感知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;和（2）在细胞外基质中没有足够的刚度，这些 不会发生壁张力的变化。从本质上讲，我们认为这是壁张力的变化-而不是 瞬时收缩本身-在充盈期间驱动传入流出。因此，壁的任何变化 顺应性将对膀胱充盈的感觉具有显著影响。这一概念只关注 膀胱的机械性能，而不推测不同细胞类型的作用 参与信号本身。通过首先了解膀胱壁顺应性如何改变感觉， 然后深入研究改变遵守的机制，从而改善我们的工作， 膀胱功能障碍的知识。具体目的是：1）确定组成和机械 脱细胞细胞的细胞外基质和完整膀胱的性质;和2）阐明脱细胞的细胞外基质和完整膀胱的性质。 膀胱壁僵硬度、膀胱充盈度和感觉流出至CNS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、神经泌尿学、统计学和临床泌尿学方面， 良性泌尿生殖系统疾病研究员，萨拉罗卡比安卡医生。罗卡比安卡医生有着独特的专业知识 在软生物组织机械表征、微观结构量化和数学 软组织建模。这个由博蒙健康和密歇根州立大学组成的团队， 彼此靠近，形成密歇根泌尿科跨学科中心 研究和教育（MI-CURE）。除了强大的良性泌尿外科研究计划， 创新和尖端的方法，MI-CURE有一个令人兴奋的教育丰富计划， 培训和指导所有级别的成人学习者，从高中生到医科学生，以帮助扩大 促进良性泌尿外科研究。MI-CURE由既定的科学家-医生团队共同指导 Lamb博士和Chancellor博士，有明确的沟通和协调计划。在一起， 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.