We hypothesize that there is a unifying mechanism associated with acute or chronic factors that damage the impermeability barrier that normally protects the bladder. Thus, we propose that increased permeability of the bladder is a root cause of many benign bladder diseases. (1) In bladder regeneration, the race between healing and fibrosis is tipped in favor of fibrosis by permeability of the nascent organ to urine, and we will investigate with animal models how decreasing permeability of the regenerating bladder facilitates healing. (2) In IC/PBS, depolarization of sensory nerves and structural changes induced by leakiness underlie that pathology. Comorbidity studies suggest that a reciprocal relationship exists between bowel and bladder such that changes in one induces permeability changes in the other, and animal studies of this reciprocity will reveal mechanisms relevant to clinical populations. Increased permeability may be a factor in OAB as well. We, therefore, plan a clinical study to determine the role of increased permeability in IC/PBS and CPP and LUTS as a function of aging.