Diabetic Uropathy Pathobiology Site

糖尿病尿路病病理生物学网站

• 批准号: 7552818
• 负责人: Firouz Daneshgari
• 金额: $ 4.4万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7552818
• 关键词: 4-Hydroxy-Tamoxifen; Adult; Advisory Committees; Affect; African; Age-Years; American; Animal Model; Animals; Appendix; Autonomic Pathways; Bioinformatics; Bladder; Bladder Dysfunction; Characteristics; Clinical; Complications of Diabetes Mellitus; Conscious; Core Facility; DNA; Data; Development; Diabetes Mellitus; Disease; Esthesia; Free Radicals; Functional disorder; Gastroparesis; Generations; Guidelines; Habits; Heterogeneity; Hyperglycemia; Hypertrophy; In Vitro; Incidence; Laboratories; Manganese Superoxide Dismutase; Metabolic; Modeling; Mouse Strains; Mus; Myopathy; Nature; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Numbness; Obesity; Overactive Bladder; Pathogenesis; Pathology; Patients; Persons; Phase; Phenotype; Play; Prevalence; Principal Investigator; Publications; Range; Rattus; Recommendation; Reporting; Research; Risk Factors; Role; Secondary to; Sexual Dysfunction; Site; Small Intestines; Smooth Muscle; Stomach; Streptozocin; Structure; Teleconferences; Therapeutic; Time; United States National Institutes of Health; Urinary Incontinence; Urinary tract infection; Urination; Validation; Week; Work; autonomic neuropathy; base; detrusor muscle; diabetic; diabetic uropathy; human old age (65+); improved; in vivo; mouse model; novel; organizational structure; programs; recombinase; response; trend; urologic; vector

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 exacerbationof STZ-induced free radical accumulation to the vasculature. Depletion of MnSOD selectively in total and arterial smooth muscle in the MnSODlox/lox, SM- CreER12 mice and MnSODlox/lox, ASM-CreERT2 mice, respectively, will be accomplished by administration of 4-hydroxytamoxifento 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.

糖尿病性泌尿病是一系列令人衰弱的泌尿科并发症（例如膀胱功能障碍）的一个术语， 尿失禁，尿路感染和性功能障碍，是最常见的， 糖尿病（DM）的成本高昂，但研究不足的并发症，这是一种无法治愈的疾病，至少影响20种 在美国，有百万人民的肥胖症患病率迅速上升。 糖尿病性泌尿病的治疗选择不足，在过去的50年中没有得到改善。在 对RFA-DK-05-011的反应，我们建议与糖尿病并发症的动物模型一起工作 财团的组织结构，充当“糖尿病尿道病理生物学网站”的组织结构 开发了两种新型糖尿病尿布病模型，并研究了 这些动物中糖尿病膀胱功能障碍的病理生理。 基于观察到的糖尿病对小动物膀胱功能的时间影响，我们 假设锰超氧化物歧化酶（MNSOD）的耗竭专门在平滑肌中 成年小鼠会加剧在STZ诱导的糖尿病期间自由基在平滑肌中的积累 并加速糖尿病膀胱功能障碍的代偿阶段的发作。我们假设 此外，将MNSOD的耗竭限制为动脉平滑肌将对STZ诱导的影响较小 糖尿病性膀胱功能障碍通过将STZ诱导的自由基积累的加剧限制为 脉管系统。 Mnsodlox/lox中的总体平滑肌和动脉平滑肌的MNSOD耗尽，Sm- CREER12小鼠和MnSodlox/Lox，分别将通过给药完成ASM-Creert2小鼠 在平滑肌中表达的4-羟基氧法化激活的CRE重组酶。动物会 进一步接受4-羟基莫昔芬治疗，其中一半将被STZ注射以诱导 糖尿病。将通过四个特定目的研究动物中的膀胱功能：1） 排尿习惯和有意识的囊肿中的体内膀胱功能的时间变化； 2） 糖尿病引起的膀胱肥大的形态变化的时间变化； 3）时间 逼尿肌肌肉收缩功能的改变； 4）传入和 传出的自主途径支配膀胱。 首席研究员和研究团队在成为一部分 自2003年以来现有的AMDCC，并且在NIH的主持下运行良好，转向和 AMDCC的外部咨询委员会。