RENAL AND CELLULAR STUDIES IN TYPE I DIABETIC PATIENTS

I 型糖尿病患者的肾脏和细胞研究

• 批准号: 7951644
• 负责人: MICHAEL S MAUER
• 金额: $ 0.51万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7951644
• 关键词: Behavior; Biopsy; Blood Pressure; Cells; Clinical; Clinical Research; Computer Retrieval of Information on Scientific Projects Database; Cross-Sectional Studies; Cultured Cells; DNA; Development; Diabetic Nephropathy; Electrons; Enzymes; Evaluation; Fibroblasts; Funding; Genetic Variation; Glucose Transporter; Grant; Growth Factor; Hyperglycemia; In Vitro; Individual; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Failure; Lesion; Link; Longitudinal Studies; Measures; Microscopic; Monozygotic twins; Patients; Phenotype; Process; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Marker; Siblings; Skin; Sodium-Hydrogen Antiporter; Source; United States National Institutes of Health; base; diabetic; diabetic patient; extracellular; mRNA Expression; non-diabetic; repository; type I diabetic

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Diabetic nephropathy (DN) is the leading cause of renal failure, yet pathogenetic understanding remains limited. Objectives of these studies are (a) to develop risk markers based on in vitro studies of cells derived from individual insulin dependent diabetic (IDDM) patients, which are related to renal biopsy endpoints, (b) to ask if these markers represent genetically determined processes and (c) to define relationships between cellular (in vitro) expression of mRNA for extracellular martix (ECM) molecules, their enzymes and enzyme regulators, growth factors, glucose transporters, and sodium/hydrogen antiporter and renal structural and functional endpoints in order to explore basic pathogenic mechanisms in DN; to develop a repository of DNA and cultured cells that will allow evaluation of the cellular functional consequences of genetic variations shown to be linked to DN risk. Three patient groups will be studied: (a) early (~10 years) and long-term (~20 years) IDDM duration patients dichotomized into 2 groups with slow or rapid development of DM lesions, (b) sibling pairs concordant for IDDM, and (c) identical twins discordant for IDDM. DN will be quantitated morphometrically, and factored for duration or expressed as a rate determined by 2 biopsies 5 years apart. The primary endpoint will be mesangial volume fraction [Vv(Mes/glom)] measured by electron microscopic morphometric analysis. Cross-sectional studies of long-term IDDM patients will allow the identification of cellular markers associated with very rapid or very slow development of DN lesions and clinical renal abnormalities. Longitudinal studies (5 year) in shorter-term "fast" and "slow-track" patients and IDDM sibling pairs will allow factoring for glycemia and blood pressure and other "environmental variables." Cultured skin fibroblasts (SF) from individual patients will be evaluated for mRNA expression for the above listed molecules using reverse transcriptase polymerase chain reaction. SF are selected since changes in their phenotype occur in "fast-track" IDDM patients and are correlated in sibling pairs. These studies will determine the relationship of DN lesions to SF behavior and evaluate whether this behavior is concordant in IDDM sibling pairs who are concordant for DN lesions. SF from nondiabetic identical twins will answer whether hyperglycemia is necessary for the expression of cellular markers of DN risk.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 糖尿病肾病（DN）是肾衰竭的主要原因，但其发病机制的了解仍然有限。 这些研究的目标是 (a) 基于对个体胰岛素依赖型糖尿病 (IDDM) 患者的细胞进行体外研究，开发与肾活检终点相关的风险标记物，(b) 询问这些标记物是否代表遗传决定的过程(c) 定义细胞外基质 (ECM) 分子、其酶和酶调节剂、生长因子、葡萄糖转运蛋白和钠/氢逆向转运蛋白的 mRNA 的细胞（体外）表达与肾脏结构和功能终点之间的关系，以便探讨DN的基本发病机制；开发 DNA 和培养细胞库，以评估与 DN 风险相关的遗传变异对细胞功能的影响。 将研究三个患者组：(a) 早期（~10 年）和长期（~20 年）IDDM 病程患者分为 DM 病变缓慢或快速发展的 2 组，(b) IDDM 一致的兄弟姐妹对， (c) IDDM 不一致的同卵双胞胎。 DN 将通过形态计量学进行定量，并考虑持续时间或表示为由间隔 5 年的 2 次活检确定的比率。 主要终点是通过电子显微镜形态测量分析测量的系膜体积分数[Vv(Mes/glom)]。 对长期 IDDM 患者的横断面研究将能够识别与 DN 病变快速或缓慢发展以及临床肾脏异常相关的细胞标记物。 对短期“快速”和“慢速”患者以及 IDDM 兄弟姐妹的纵向研究（5 年）将考虑血糖、血压和其他“环境变量”。 将使用逆转录酶聚合酶链式反应评估来自个体患者的培养的皮肤成纤维细胞(SF)的上述分子的mRNA表达。 选择 SF 是因为其表型变化发生在“快速通道”IDDM 患者中，并且在兄弟姐妹中相关。 这些研究将确定 DN 病变与 SF 行为的关系，并评估这种行为在 DN 病变一致的 IDDM 兄弟姐妹中是否一致。 来自非糖尿病同卵双胞胎的 SF 将回答高血糖是否是 DN 风险细胞标志物表达所必需的。