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Impact of Diabetes on Urothelial Progenitor Cell Function and Healing
Recurrent urinary tract infections (UTIs) have a profoundly negative impact on quality of life in diabeticwomen. Up to 50% of diabetic women will develop a UTI, which is twice as high as non-diabetic women.Further, diabetic women have a two-fold higher risk of suffering from recurrent UTIs throughout their lifetime.Patients with diabetes are more prone to developing severe manifestations of UTI, including gas-forming(emphysematous) cystitis, kidney infections, and death. There remains an absence of targeted treatmentstrategies to decrease the incidence of UTI in diabetic patients largely because the underlying basis for theincreased risk of UTI in diabetic patients is not known. As such, diabetic women are treated with chronicantibiotics, leading to substantial economic burden as well as an increase in multidrug-resistant UTIs.Paramount to UTI prevention is maintenance of the complex urothelial barrier that lines the bladder lumen.Diabetes causes impaired progenitor cell function and wound healing in many organs, raising the possibilitythat diabetes affects urothelial progenitors as well. It is our overarching hypothesis that diabetes causesimpaired urothelial progenitor cell function and regeneration, loss of barrier function, and increased risk for UTI. This pilot project will test the specific hypothesis that diabetes results in loss of urothelial progenitor cellfunction and impaired urothelial regeneration after treatment of UTI. We will test this hypothesis using twomouse models of type II diabetes: BTBR ob/ob mice and high-fat diet (HFD)-induced diabetic mice. In Aim 1,we will test the hypothesis that urothelial regeneration after treatment of UTI is impaired in BTBR ob/ob micecompared to BTBR wild-type (WT) mice. In Aim 2, we will test the hypothesis that urothelial progenitor cellfunction is impaired in diabetic mice compared to non-diabetic mice. This proposal employs amultidisciplinary team science approach to study the impact of diabetes on urothelial progenitor cell functionand regeneration. We anticipate that these studies will produce clinically relevant data that can be used as astarting point to evaluate the effects and causes of recurrent UTI in human diabetic patients.

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