Renal & Cellular Studies in Type 1 Diabetic Patients

描述(由申请人提供)：目标是(1)基于对1型D型患者(PTS)来源的细胞的体外研究，进一步开发糖尿病肾病(DN)风险标记物，(B)询问这些标记物是否代表遗传决定的过程，以及(C)确定这些预测因素是否依赖于体内细胞对D的暴露。这些标记物将通过(I)它们与已知的病理生理模式的相关性和(Ii)候选分子和判别表达模式的微阵列筛选来寻找。研究将分为5组：(1)早期(10年)和(2)长期(20年)糖尿病肾病患者，分为两组：(1)糖尿病肾病病变和蛋白尿进展缓慢或迅速的两组；(3)符合1型D型的同胞对；(4)1型D型肾移植受者及其活体供者；(5)通过成功的胰腺移植至少5年治愈的糖尿病肾病快速发展的1型D型患者。糖尿病肾病将通过形态计量学进行量化，并根据持续时间进行因子分析，或以相隔5年的2次活检确定的比率来表示。主要终点将是系膜体积分数[VV(MES/GLOM)]。对长期PTS的横断面研究将允许识别与糖尿病肾病风险相关的标记物。短期的纵向研究(5年)将在检测到蛋白尿的任何增加之前确定这些标志物是否存在。皮肤成纤维细胞(SF)之所以被选择，是因为它们的表型在“慢速”、“快进”和对照组之间存在差异，并且它们的表型在兄弟姐妹中是相关的。选择近端肾小管上皮细胞(PTEC)是因为肾小管基底膜的变化与肾小球的变化平行。这些研究将确定糖尿病肾病与SF和PTEC行为(基因表达水平和模式；细胞增殖和细胞周期)的关系，并评估这些行为是否受基因调控。这些研究将提供糖尿病肾病风险的标记物和预测因子，确定它们是受基因调控还是依赖于先前接触D，并确定糖尿病肾病的致病途径。

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.