Diabetic Uropathy Pathobiology Site

糖尿病尿路病病理生物学网站

基本信息

批准号：
7915663
负责人：
Firouz Daneshgari
金额：
$ 34.63万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-30 至 2011-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7915663
关键词：
4-Hydroxy-Tamoxifen Adult Advisory Committees Affect African Age-Years American Animal Model Animals 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 Persons Phase Phenotype Play Prevalence Principal Investigator Publications 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 Work autonomic neuropathy base detrusor muscle diabetic diabetic patient diabetic uropathy human old age (65+)improved in vivo meetings mouse model novel organizational structure programs recombinase response trend urologic vector

项目摘要

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.

描述（由申请人提供）：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的动物模型合作，以作为“糖尿病性尿素病理生物学部位”的工作，以开发两种新颖的糖尿病尿症模型，并研究糖尿病学病理学机制的动物糖尿病学胰腺胰腺胰腺胰腺胰腺胰蛋白酶的机制。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，通过限制加剧STZ诱导的自由基积累对脉管系统的影响。 MNSodlox/Lox，SmCreert2小鼠和MnSodlox/Lox，ASM-Creert2小鼠的MNSOD在总和平滑肌中有选择性地消耗，将通过给予4-羟基tamoxifen来激活以平滑肌肉表达的CRE重组酶来实现。这些动物将通过4-羟基莫昔芬治疗进一步治疗，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）由排尿习惯和有意识的囊肿方法进行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。