Medical College of Wisconsin Mickle Laboratory

Urothelial cells play an active role in bladder physiology by responding to physical/chemical stimuli and signaling to sensory neurons and other cell types in the bladder. Numerous bladder diseases affecting millions of people, including overactive bladder, pain related to recurrent bladder infection, chemotherapeutic cystitis, and bladder pain syndrome, have been suspected to disrupt urothelial sensory signaling, leading to pathological changes to sensory signaling, including pain. While it has been accepted that urothelial cells play a role in bladder sensory function, it is unclear how these cells contribute to the sensation of filling and how it is altered under painful conditions. To unravel the role of urothelial cells in bladder nociception and sensory dysfunction, we have developed a novel mouse model that allows for direct stimulation of urothelial cells using optogenetics, light activated proteins. This project broadly focuses on functionally and molecularly identify the population of sensory neurons responding to direct urothelial stimulation of sensory nerve activity in normal and inflammatory conditions. We are using in vivo electrophysiology, fMRI and wireless implantable LEDs paired with behavior to study this question.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is associated with increased voiding frequency, nocturia, bladder fibrosis, and chronic pelvic pain. It affects between 2.5 to 6.7% of women in the United States. Current treatment options are ineffective for all patients and are associated with detrimental side effects. One understudied signaling peptide/hormone in IC/BPS is angiotensin II (Ang II). In addition to its role in vasoconstriction, water retention, and stress response, Ang II contributes to several diseases by promoting oxidative stress, proinflammatory cytokine release, and fibrosis, resulting in increased nociception and sensory sensitivity. However, compared to other organ systems (cardiac, kidneys, and lungs), relatively little is known about the function of Ang II signaling in the bladder under pathophysiologic conditions. There are several intriguing links between IC/BPS pathology and angiotensin signaling. 1) IC/BPS patients have increased infiltration of mast cells, which represent a source of increased renin and Ang II. 2) IC/BPS patients and animal disease models have increased bladder oxidative stress, and angiotensin signaling increases ROS production. 3) IC/BPS patients have increased expression of inflammatory mediators, which can be released by Ang II downstream signaling. 4) Fibrosis is observed in patients and animal models of IC/BPS, and Ang II signaling has been linked to fibrosis in heart, lungs, liver, and kidneys. Given the foundation of IC/BPS research demonstrating increases in local mast cells/macrophages, oxidative stress, inflammatory mediators, fibrosis, and the wealth of literature describing similar Ang II molecular signaling events in other tissues, we believe it is essential to further explore the role of Ang II in bladder diseases.