Renal & Cellular Studies in Type 1 Diabetic Patients

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• 批准号: 7030214
• 负责人: S. Michael Mauer
• 金额: $ 63.84万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-14 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7030214
• 关键词: albuminuria; biomarker; biopsy; clinical research; diabetic nephropathy; disease /disorder proneness /risk; fibroblasts; gene expression; genetic susceptibility; human subject; insulin dependent diabetes mellitus; kidney cell; kidney function; longitudinal human study; microarray technology; polymerase chain reaction; siblings; tissue /cell culture

DESCRIPTION (provided by applicant): Objectives are (1) to further develop diabetic nephropathy (DN) risk markers based on in vitro studies of cells derived from type 1 D patients (pts), (b) to ask if these markers represent genetically determined processes and (c) to determine if these predictors are dependent on in vivo cellular exposure to D. These markers will be searched for by (i) their relevance to known pathophysiologic patterns and by (ii) microarray screening for candidate molecules and discriminant expression patterns. Five groups will be studied: (1) early (10 yrs) and (2) long-term (20 yrs) D duration pts dichotomized into 2 groups with slow or rapid development of DN lesions and albuminuria, (3) sibling pairs concordant for type 1 D, (4) type 1 D kidney transplant recipients and their living donors, (5) type 1 D pts with rapid development of DN who have been cured of D by successful pancreas transplant for at least 5 yrs. DN will be quantitated morphometrically, and factored for duration or expressed as a rate determined by 2 biopsies 5 yrs apart. The primary endpoint will be mesangial volume fraction [Vv(Mes/glom)]. Cross-sectional studies of long-term pts will allow the identification of markers associated with DN risk. Longitudinal studies (5 yr) in shorter-term will determine if these markers are present before any increase in albuminuria is detectable. Skin fibroblasts (SF) were selected since differences in their phenotype occur between "slow-track," "fast-track" and controls and their phenotypes are correlated in sibling pairs. Proximal tubular epithelial cells (PTEC) are selected because tubular basement membrane changes in D parallel those in glomeruli. These studies will determine the relationship of DN to SF and PTEC behaviors (gene expression levels and patterns; cell proliferation cell cycle), and evaluate whether these behaviors are genetically regulated. These studies will provide markers and predictors of DN risk, determine if these are genetically regulated or dependent on prior exposure to D, and identify DN pathogenetic pathways.

描述（由申请人提供）：基于基于1型患者（PTS）的细胞的体外研究，进一步发展糖尿病性肾病（DN）风险标志物的目的是（b），以确定这些预测的过程是否代表这些预测因素是否依赖于这些预测因素对这些预测依赖于这些标记的依赖性（i Interive to d. d. d. d. d. d. d. d.模式和（ii）候选分子和判别表达模式的微阵列筛选。 Five groups will be studied: (1) early (10 yrs) and (2) long-term (20 yrs) D duration pts dichotomized into 2 groups with slow or rapid development of DN lesions and albuminuria, (3) sibling pairs concordant for type 1 D, (4) type 1 D kidney transplant recipients and their living donors, (5) type 1 D pts with rapid development of DN who have been cured of D by成功的胰腺移植至少5年。 DN将通过形态计量定量，并考虑持续时间，或以2年5年5年的2年活检确定的速率表示。主要端点将是膜的体积分数[VV（MES/GLOM）]。 长期PT的横断面研究将允许鉴定与DN风险相关的标记。较短期限的纵向研究（5年）将确定在可检测到蛋白尿的任何增加之前是否存在这些标记。选择皮肤成纤维细胞（SF），因为其表型的差异发生在“慢轨”，“快速轨道”和对照及其表型之间的差异与兄弟姐妹对相关。选择近端管状上皮细胞（PTEC）是因为肾小球中的管状地下膜变化。这些研究将确定DN与SF和PTEC行为的关系（基因表达水平和模式；细胞增殖细胞周期），并评估这些行为是否受到遗传调节。 这些研究将提供DN风险的标志物和预测因子，确定这些研究是否受到遗传调节或取决于事先暴露于D，并确定DN致病途径。