Our long term goals are to uncover the mechanisms underlying diabetic bladder dysfunction (DBD), one of the most common and incapacitating complications of the diabetes mellitus (DM), and develop curative therapies for DBD. Knowledge of the pathophysiology and mechanisms of DBD, a range of abnormalities characterized mainly by poor emptying of the bladder and urinary incontinence, has been inadequate for development of effective treatments. In our previous and ongoing studies of T1D-related bladder dysfunction (T1D-BD) in rodents, we have identified the time dependence of the multiple manifestations of DBD, involving early compensatory changes associated with osmotically-induced polyuria (storage problems) and later decompensatory changes manifest as voiding problems. Based on this work and results of other groups, we hypothesize that: i) In the early stage of DM, osmotically induced polyuria causes rapid hypertrophy and remodeling of the bladder involving both neurogenic and myogenic components, leading to compensatory storage problems. ii) In the later stage of DM, effects of long-term hyperglycemia on the bladder, beyond polyuria, cause irreversible damages to the functions of nerves and muscles, leading to decompensatory voiding problems of the bladder. iii) The damages to LUT tissues in late stage DM are caused mainly by accumulation of oxidative stress products induced partly by hypertrophy and mostly by prolonged hyperglycemia. Drawing on our established track record using small rodent models of LUT dysfunction, and using three innovative approaches created recently in our laboratory [urinary diversion (UD) from the ureters to the cervix, assessment of afferent sensory function of the bladder, and transgenic mice with conditional, smooth muscle-selective deletion of the manganese superoxide dismutase (MnSOD) gene], we will test our hypotheses in two Specific Aims: SA#1- To distinguish the roles of hyperglycemia and polyuria in the temporal progression of T1D-BD, by comparing the functional and neurochemical changes that follow streptozotocin (STZ)-induced DM, diuresis, or sham treatment in rats with or without UD. SA#2- To determine the mechanistic role of oxidative stress in the pathogenesis of T1D-BD, by comparing the functional, morphological and molecular changes in the bladder during the temporal progression of STZ induced DM in mice with smooth muscle-selective deletion of MnSOD, global overexpression of MnSOD, or drug-induced attenuation of oxidative stress or neuropathy. Our research team and collaborators have one of the highest levels of expertise in translational studies of DBD. Through this collaboration, the data generated from this proposal will provide Significant comprehensive insights into the pathogenesis of DBD and on potential therapeutic targets to prevent or treat DBD effectively.

Public Health Relevance

Diabetes mellitus (DM) is a group of debilitating and costly diseases with multiple serious complications that afflict 25 million people in the U.S. and is estimated to affect 366 million worldwide by 2030. Diabetic bladder dysfunction (DBD), characterized by poor emptying of the bladder and urinary incontinence, is among the most common and incapacitating complications of DM. However, poor knowledge of the pathophysiology and mechanisms of DBD leaves millions of patients with ineffective management options. Our research team is among the leading groups in the study of DBD. We have observed the time-dependence of multiple manifestations of DBD, and explained the natural history of DBD in animal models of DBD. Based on that work, we now propose to study the mechanisms of the bladder dysfunction at early and late stage of DBD by identification of roles of polyuria, hyperglycemia, and oxidative stress on creation of compensated and decompensated DBD. In continuation of our work on DBD, the data generated from this proposal would yield some of the most comprehensive insights into the pathogenesis of DBD and on potential therapeutic targets to prevent or treat DBD effectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083733-04
Application #
8854073
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rankin, Tracy L
Project Start
2012-05-01
Project End
2017-04-30
Budget Start
2015-05-01
Budget End
2017-04-30
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Surgery
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Wu, Liyang; Zhang, Xiaodong; Xiao, Nan et al. (2016) Functional and morphological alterations of the urinary bladder in type 2 diabetic FVB(db/db) mice. J Diabetes Complications 30:778-85
Ozer, Ahmet; Altuntas, Cengiz Z; Izgi, Kenan et al. (2015) Advanced glycation end products facilitate bacterial adherence in urinary tract infection in diabetic mice. Pathog Dis 73:
Ozer, Ahmet; Altuntas, Cengiz Z; Bicer, Fuat et al. (2015) Impaired cytokine expression, neutrophil infiltration and bacterial clearance in response to urinary tract infection in diabetic mice. Pathog Dis 73:
Tomechko, Sara E; Liu, Guiming; Tao, Mingfang et al. (2015) Tissue specific dysregulated protein subnetworks in type 2 diabetic bladder urothelium and detrusor muscle. Mol Cell Proteomics 14:635-45
Liu, Guiming; Elrashidy, Rania A; Xiao, Nan et al. (2015) Bladder function in mice with inducible smooth muscle-specific deletion of the manganese superoxide dismutase gene. Am J Physiol Cell Physiol 309:C169-78
Bicer, Fuat; Kim, Jin Young; Horowitz, Andrew et al. (2014) Assessment of bladder sensation in mice with a novel device. Urology 84:490.e1-6
Liu, Guiming; Daneshgari, Firouz (2014) Diabetic bladder dysfunction. Chin Med J (Engl) 127:1357-64
Xiao, Nan; Wang, Zhiping; Huang, Yexiang et al. (2013) Roles of polyuria and hyperglycemia in bladder dysfunction in diabetes. J Urol 189:1130-6
Daneshgari, Firouz; Brown, Jeanette S; Kusek, John W et al. (2009) Urological complications of obesity and diabetes. J Urol 182:S1