Renal & Cellular Studies in Type 1 Diabetic Patients

描述（由申请人提供）：目的是(1)基于1型D患者（pts）细胞的体外研究进一步开发糖尿病肾病（DN）风险标志物，(b)询问这些标志物是否代表遗传决定的过程，(c)确定这些预测因子是否依赖于体内细胞暴露于D。这些标志物将通过(i)它们与已知病理生理模式的相关性以及（ii）微阵列筛选候选分子和鉴别表达模式来搜索。将研究五组：(1)早期（10年）和(2)长期（20年）D病程患者分为两组，分别为DN病变和蛋白尿的缓慢或快速发展，(3)1型D的兄弟姐妹配对一致，(4)1型D肾移植受者及其活体供者，(5)通过成功的胰腺移植治愈DN的快速发展的1型D患者至少5年。DN将以形态计量学定量，并考虑持续时间或以间隔5年的2次活检确定的比率表示。主要终点是系膜体积分数[Vv(Mes/glom)]。长期pts的横断面研究将允许识别与DN风险相关的标志物。短期的纵向研究（5年）将在检测到蛋白尿增加之前确定这些标记物是否存在。之所以选择皮肤成纤维细胞（SF），是因为它们的表型在“慢轨”、“快轨”和对照之间存在差异，而且它们的表型在兄弟姐妹对中是相关的。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相似。这些研究将确定DN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DN风险的标志物和预测因子，确定这些标志物和预测因子是否受遗传调控或依赖于先前的DN暴露，并确定DN的发病途径。

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.