Diabetic Uropathy Pathobiology Site

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DESCRIPTION (provided by applicant): Diabetic Uropathy is a term for a range of debilitating urologic complications such as bladder dysfunction, urinary incontinence, urinary tract infection and sexual dysfunction, that are among the most common and costly, yet understudied complications of diabetes mellitus (DM), an incurable disease that affects at least 20 million people in the U.S. and is rising in prevalence with the rapidly rising prevalence of obesity. Therapeutic options for diabetic uropathy are inadequate and have not improved over the last 50 years. In response to RFA-DK-05-011, we propose to work with the Animal Models of Diabetic Complications Consortium's organizational structure to function as the 'Diabetic Uropathy Pathobiology Site" to participate in development of two novel mice models of diabetic uropathy and to investigate the mechanisms of the pathophysiology of diabetic bladder dysfunction in these animals. Based on the observed temporal effects of diabetes on the bladder function in small animals, we hypothesize that depletion of manganese superoxide dismutase (MnSOD) specifically in smooth muscle of adult mice will exacerbate accumulation of free radicals in smooth muscle during STZ-induced diabetes and accelerate the onset of the decompensated phase of diabetic bladder dysfunction. We hypothesize further that limiting depletion of MnSOD to arterial smooth muscle will have a lesser effect on STZ-induced diabetic bladder dysfunction by limiting exacerbation of STZ-induced free radical accumulation to the vasculature. Depletion of MnSOD selectively in total and arterial smooth muscle in the MnSODlox/lox, SMCreERT2 mice and MnSODlox/lox, ASM-CreERT2 mice, respectively, will be accomplished by administration of 4-hydroxytamoxifen to activate Cre recombinase expressed in the smooth muscle. The animals will be further treated with 4-hydroxytamoxifen treatment, and half of them will be injected with STZ to induce diabetes. The bladder function in the animals will be studied via four specific aims to examine: 1) the temporal alterations in the in-vivo bladder function by micturition habits and conscious cystometry; 2) the temporal course of morphological changes in diabetes-induced bladder hypertrophy; 3) temporal alterations in the contractile function of the detrusor muscle; 4) the temporal alterations in afferent and efferent autonomic pathways innervating the bladder. The Principal Investigator and the research team have a productive track record in being a part of the existing AMDCC since 2003 and have functioned well under the auspices of the NIH, and the Steering and External Advisory Committees of the AMDCC.