MI-CURE Research Project

摘要

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.