Diabetic Uropathy Pathobiology Site

糖尿病尿路病病理生物学网站

基本信息

批准号：
7998852
负责人：
Firouz Daneshgari
金额：
$ 7.95万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-10 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7998852
关键词：
4-Hydroxy-Tamoxifen Adult Advisory Committees Affect Animal Model Animals Authorization documentation Autonomic Pathways Bioinformatics Bladder Bladder Dysfunction Budgets Cell Line Child Cities Clinic Clinical Research Clinical Trials Complications of Diabetes Mellitus Conscious Core Facility Data Development Diabetes Mellitus Disclosure Disease Enrollment Face Free Radicals Functional disorder Generations Goals Guidelines Habits Human Resources Human Subject Research Hypertrophy Instruction Last Name Letters Literature Manganese Superoxide Dismutase Manuscripts Medicine Metabolic Minority Modeling Monitor Mouse Strains Mus Names Obesity Organ Persons Phase Phenotype Postdoctoral Fellow Prevalence Principal Investigator Printing Progress Reports Publications Recommendation Registries Research Research Project Grants Resource Sharing Resources Role Safety Sexual Dysfunction Site Smooth Muscle Streptozocin Structure Teleconferences Therapeutic Time United States National Institutes of Health Universities Urinary Incontinence Urinary tract infection Urination Validation Vertebrates Wisconsin Woman Work base c new college commercialization detrusor muscle diabetic diabetic uropathy human embryonic stem cell human subject protection improved in vivo meetings mouse model novel organizational structure performance site programs recombinase research study response urologic

项目摘要

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.

糖尿病尿道病是一系列衰弱的泌尿科并发症，例如膀胱功能障碍，尿失禁，尿道感染和性功能障碍，是最常见且最昂贵的，但最常见的，但正在研究的并发症，糖尿病（DM）的快速疾病，至少会影响20亿人，并且在20亿人中被预言。肥胖。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。为了响应RFA-DK-05-011，我们建议与糖尿病并发症联盟的动物模型一起工作，以作为“糖尿病性泌尿病病理生物学部位”的作用，以开发两种新型糖尿病尿症模型，并研究这些动物中糖尿病膀胱功能障碍的病理生理。基于糖尿病对小动物膀胱功能的观察到的时间影响，我们假设在成年小鼠平滑肌中特别是在STZ诱发的糖尿病和加速糖尿病的糖尿病中，锰超氧化物歧化酶（MNSOD）会加剧平滑肌中平滑肌自由基在平滑肌中的自由基积累加剧。我们进一步假设将MNSOD限制为动脉平滑肌的耗竭将对STZ诱导的糖尿病性膀胱功能障碍产生较小的影响，通过限制对STZ诱导的自由基积累的加剧对脉管系统的影响。 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分别将通过给予在平滑肌中表达的4-羟基氧莫昔芬激活CRE重组酶来完成。动物会进一步接受4-羟基莫昔芬治疗，其中一半将用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）糖尿病诱导的膀胱肥大的形态变化的时间变化； 3）迫切肌肉收缩功能的时间改变； 4）神经膀胱的传入和传出自主途径的时间变化。自2003年以来，首席研究员和研究团队在成为现有AMDCC的一部分方面具有富有成效的记录，并且在NIH的主持下以及AMDCC的指导和外部咨询委员会的运作良好。