Pannexin 1 Channel, a Novel Molecular Mediator and Potential Therapeutic Target for Interstitial Cystitis
Abstract
This proposal specifically address the “Interstitial Cystitis” (IC) FY20 PRMRP Topic Area and is in line with the encouragement areas of research in the etiology of IC and evaluation of novel treatment options for IC patients. Interstitial cystitis refers to a chronic and debilitating bladder condition characterized by symptoms that include urinary urgency, frequency, and pelvic pain observed in the absence of urinary tract infection or other diseases that may cause these symptoms. More than 4 million people in the United States suffer from IC, and although IC is typically not life-threatening, its symptoms are hard to tolerate and cause significant emotional distress and impact patients’ quality of life. The etiology of IC is not entirely known. Among possible triggers are infection, autoimmune response, allergic reaction, neurogenic inflammation, urothelial dysfunction, and genetic predisposition. Accumulating evidence obtained from basic and clinical studies suggest that increase in permeability of the urothelium contributes to the onset and perpetuation of IC symptoms. The urothelium forms the innermost layer of the bladder and protects the underlying bladder tissues from noxious urine contents, such as high K+, urea, other toxic substances, and pathogens. Molecular and histological studies of bladder biopsies indicate that a great part of IC patients have a dysfunctional urothelial barrier. Treatment approaches focused on repairing the urothelial barrier are not always effective, which highlights the need for better understanding the underlying mechanisms. The studies in this project will address this gap in our knowledge. We proposed that pannexin 1 (Panx1) channels play a central role in mechanisms that trigger IC in the context of urothelial barrier disruption. Panx1 is receiving increasing attention for its emerging roles in bladder physiology and pathology, and has unique properties that ideally place it at the center of events triggered by chronic exposure to urinary K+, as would occur when the urothelial barrier is breached. Panx1 channels have been shown to be activated by K+ independently of membrane depolarization and to participate in mechanisms of intercellular signaling and inflammation by providing a conduit for controlled cellular ATP release and by activating the inflammasome complex. Studies proposed in this project will specifically investigate the extent to which chronic infiltration of urinary K+ into the bladder wall generates a conducive environment for abnormal Panx1 channel activation and expression, which augment proinflammatory responses, intercellular signaling and stimulation of bladder sensory fibers that ultimately lead to IC and its symptoms. The specific aims of this study are: Aim 1: Investigate the participation of pannexin 1 (Panx1) channels in mechanisms that lead to bladder sensitization, micturition dysfunction and pelvic pain in a stress-induced IC model with disruption of the urothelial barrier. Aim 2: Determine the potential of Panx1 channels as novel therapeutic targets for interstitial cystitis associated with urothelial barrier dysfunction. Studies will be conducted with a clinically relevant animal model of stress, a factor with major relevance in modern society and particularly in the lives of military personnel and their families, and that is also known to cause disruption of the urothelial barrier. Experimental approaches will include physiological assessments of bladder function, pelvic and bladder pain, and molecular, biochemical, and histological analyses of changes in Panx1, inflammasome components and pro-inflammatory mediators, changes in bladder morphology, presence of inflammatory cell infiltrates and interstitial edema, and spinal c-fos activation (indication for bladder sensory fibers activation). Therapeutic effects of Panx1 channel blockers and Panx1 silencing using intravesical delivered liposome containing Panx1-siRNA will be evaluated in the animal mo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110465
Entities
People
- Sylvia Suadicani
Organizations
- Albert Einstein College of Medicine
- United States Army