Mitochondrial and Oxidative Stress in Type 1 Diabetes

描述（由申请人提供）：糖尿病肾病（DN）是1型糖尿病（T1 DM）的主要并发症和肾衰竭的主要原因，在其大部分自然史中是沉默的。一些证据表明，线粒体（mt）功能异常和由此产生的氧化应激增加是DN发病机制的重要组成部分。皮肤成纤维细胞（SF）的体外行为反映了DN的风险。来自T1 DM患者SF的微阵列基因表达数据显示，在快速与缓慢DN发展的患者中，mt途径上调，与通过增加活性氧（ROS）产生的氧化应激一致。此外，与正常对照相比，在无并发症的T1 DM患者中观察到类似的定向途径基因表达增加，这些发现与T1 DM本身发病机制相关的细胞过程或体内高血糖症的体外细胞记忆一致。R21应用旨在进一步研究这些观察结果，代表了长期对DN研究感兴趣的肾病学家，糖尿病学家和生物统计学家以及具有mt功能和氧化应激专业知识的基础生物化学家之间的创新伙伴关系。本文概述的研究将测试氧化应激（反映线粒体或细胞溶质ROS产生和清除的不平衡）是否在快速与缓慢DN发展的T1 DM患者以及缓慢DN发展的患者和正常对照的SF中明显。如果是这样，这将提供设计进一步研究所需的初步数据，这些研究将测试这些SF行为变量是否：a）遗传; B）依赖于T1 DM暴露前的SF;和（c）存在于外周血单核细胞中，因此，可作为方便的疾病风险生物标志物。总之，这些研究可以提供准确、方便的DN和T1 DM风险的替代标志物以及对DN和T1 DM发病机制的认识，并为预防T1 DM及其并发症提供新的治疗靶点。

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN), the leading complication of type 1 diabetes (T1DM) and the leading cause of kidney failure, is silent through most of its natural history. Several lines of evidence suggest that abnormalities in mitochondrial (mt) function and resultant increased oxidative stress are important components of DN pathogenesis. Skin fibroblasts (SF) in vitro behaviors reflect DN risk. Microarray gene expression data from SF of T1DM patients showed upregulation of mt pathways in patients with rapid vs. slow DN development, consistent with oxidative stress through increased reactive oxygen species (ROS) production. Moreover, similar directional pathway gene expression increases were seen in T1DM pts without complications as compared to normal controls, these findings consistent with cellular processes associated with the pathogenesis of T1DM per se or with in vitro cellular memory for in vivo hyperglycemia. This R21 application which aims to further pursue these observations, represents an innovative partnership between nephrologists, diabetologists, and biostatisticians long interested in DN research and basic biochemists with expertise in mt function and oxidative stress. The research outlined here will test whether oxidative stress, reflecting mt or cytosolic imbalances of ROS production and removal, is evident in SF of T1DM patients with rapid versus slow DN development and in patients with slow DN development and normal controls. If so, this would provide the preliminary data needed to design further studies that would test whether these SF behavioral variables are: a) inherited; b) dependent on SF prior exposure to T1DM; and (c) present in peripheral blood mononuclear cells, and, thus, adaptable as convenient disease risk biomarkers. In summary, these studies could provide accurate and convenient surrogate markers of DN and T1DM risk as well as pathogenetic insights into DN and T1DM, and could provide new treatment targets for prevention of T1DM and its complications.