Signal integration by specialized mesenchyme in urothelial homeostasis and Interstitial Cystitis / Bladder Pain Syndrome

Summary Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a debilitating disease of unknown etiology that affects millions, with an estimated 2.7-6.3% of women, who are disproportionately affected, meeting the diagnostic criteria. IC/BPS is characterized by persistent pelvic pain, pressure, or discomfort arising from the urinary tract and is accompanied by increased urgency and frequency of urination. These symptoms are highly disruptive to everyday life, and current treatments fail to address the underlying causes of IC/BPS, which remain enigmatic. Pain management is an essential aspect of treatment, and incorporates opioid-based analgesia in 28% of patients within a month of diagnosis, presenting significant risks of addiction. Whereas its pathogenesis remains unclear, IC/BPS is commonly associated with bladder sensory hyperinnervation, which aligns with the clinical picture of increased sensitivity to pressure or noxious stimuli. Effective treatment, however, must also address dysfunction of the protective bladder epithelium (urothelium), as indicated by the association of flare-ups (up to 1/3) with urinary tract infections that injure the urothelium and by the near total loss of the urothelial barrier in severe IC/BPS with Hunner’s lesions (10-20% of patients). Our mouse data, including scRNA-Seq (single cell RNA sequencing), pinpoint a specialized compartment of bladder mesenchyme that functions in the regulation of both bladder sensory innervation and urothelial integrity. This specialized mesenchyme, termed SAM (sensory nerve-associated mesenchyme), appears to integrate signaling inputs from the general circulation, from neighboring bladder cell types including urothelium, and from nociceptive neuronal termini to generate a mesenchymal instruction set that underlies sexual dimorphism in bladder nociception and maintenance of urothelial integrity. Our preliminary data also present a molecular compendium based on scRNA-Seq of samples from normal human and IC/BPS patient bladders. This IC/BPS cell atlas suggests that SAM dysfunction in signal processing and integration may constitute a central common feature underlying and unifying the diverse manifestations of IC/BPS, and we propose to confirm and extend these preliminary findings by expanding our cell atlas to include samples from multiple disease stages. Further investigation based on these findings may identify SAM-specific signaling pathways as novel therapeutic targets for IC/BPS intervention. Aim 1 of our proposal will focus on local and systemic signals that elicit SAM production of neurotrophins, whereas Aim 2 presents preliminary studies showing that sensory neurons innervatint the bladder can profoundly affect the urothelium, likely acting through neuropeptide signaling to SAM. Modulating these signaling pathways with non-toxic pharmacologic agents in animal models of IC/BPS, as outlined in Aim 3, will provide the basis for effective new treatments, which may obviate the need for opioid use in pain management, thereby eliminating the risk of addiction.