Cystitis-induced bladder dysfunction and pain

Project Summary/Abstract Bladder Pain Syndrome (BPS)/Interstitial Cystitis (IC) is a chronic pelvic pain disorder with at least one urinary symptom and the perception that the pain originates from the bladder. Stress exacerbates symptoms of BPS/IC. Despite intense research, we lack understanding of how structural and functional changes in the

micturition reflex are linked to BPS/IC and how stress exacerbates symptoms, thus impeding effective therapies. Addressing these challenges requires, in part: (1) a novel hypothesis involving NGF/TrkA/MAPK signaling for downstream transient receptor potential cation channel subfamily vanilloid member 4

(TRPV4)/Ca2+ activation in the sensory components of the micturition reflex; (2) innovative and multidisciplinary approaches; and (3) animal models that recapitulate the clinical signs/symptoms of BPS/IC including symptom exacerbation (flares) precipitated by psychological stress. Our laboratory is unique in the complementary use

of several relevant models to reinforce our studies including (e.g., cyclophosphamide (CYP)-induced cystitis, transgenic mice with chronic, urothelial overexpression of NGF (NGF-OE), repeated, low dose CYP (alone insufficient to produce significant symptoms) coupled with repeated variate stress (RVS) to assess how stress

can exacerbate disease. Our overall hypothesis is that increases in urinary frequency and pelvic sensation that accompany BPS/IC reflect increased expression, function and interactions of neurochemical mediators and the sensory transducer, TRPV4, in the sensory components of the micturition reflex that favor a pro-excitatory

state. Building from our previous work, the maladaptive role(s) of NGF/TrkA/p75NTR signaling and downstream activation of TRPV4/Ca2+ in the sensory components of the micturition reflex will be assessed as contributory mechanisms to BPS/IC. Aim 1: Determine if interrupting NGF/TrkA/p75NTR signaling pathways reduces voiding

frequency and pelvic pain by: reducing (1) urothelial Ca2+ events; (2) urothelial ATP release and (3) bladder afferent activity. Further interrupting NGF/p75NTR signaling reduces voiding frequency by: (1) reducing urothelial cell apoptosis; (2) promoting urothelial cell recovery and (3) maintaining transepithelial resistance.

Aim 2: Determine if disruption of NGF signaling in the micturition pathway has short- and long-term consequences on TRPV4/Ca2+ function in BPS/IC-like symptoms. The acute NGF-mediated TRPV4/Ca2+ BPS/IC-related responses include heightened urothelial Ca2+ signaling, urothelial ATP secretion and bladder

afferent nerve activity. Maladaptive, long-term NGF signaling promotes BPS/IC by increasing TRPV4 transcript and protein expression. Using three models with BPS/IC-like symptoms and a multidisciplinary, cell-tissue- systems experimental approach, we will determine: (1) underlying structural and functional changes

contributory to BPS/IC-like symptoms; (2) the influence of psychological stress on bladder function and pain and (3) novel treatments.