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.

Grant Number: 4R01DK134989-02
NIH Institute/Center: NIH
Principal Investigator: PHILIP BEACHY