Mitochondrial and Oxidative Stress in Type 1 Diabetes

描述(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，也是导致肾衰竭的主要原因，在其自然病史的大部分时间里都是沉默的。一些证据表明，线粒体功能异常和由此导致的氧化应激增加是糖尿病肾病发病机制的重要组成部分。皮肤成纤维细胞(SF)的体外行为反映了糖尿病肾病的风险。来自T1 DM患者SF的微阵列基因表达数据显示，在快速与缓慢糖尿病发展的患者中，mt通路上调，这与通过增加活性氧物种(ROS)产生的氧化应激相一致。此外，在无并发症的T1 DM患者中，与正常对照组相比，类似的定向通路基因表达增加，这些发现与T1 DM本身的发病机制相关的细胞过程或体内高血糖的体外细胞记忆相一致。这一R21应用旨在进一步进行这些观察，代表着肾病学家、糖尿病专家和长期对糖尿病肾病研究感兴趣的生物统计学家与具有MT功能和氧化应激专业知识的基础生化学家之间的创新合作伙伴关系。本文概述的研究将测试反映线粒体或细胞内ROS产生和清除失衡的氧化应激在糖尿病肾病快速发展与缓慢发展患者和正常对照组患者的SF中是否明显。如果是这样的话，这将提供设计进一步研究所需的初步数据，以测试这些SF行为变量是否：a)遗传；b)依赖SF先前接触T1 DM；以及(C)存在于外周血单个核细胞，因此适合作为方便的疾病风险生物标记物。综上所述，这些研究可以提供准确和方便的糖尿病肾病和T1 DM风险的替代标志物，以及对糖尿病和T1 DM的发病机制的深入了解，并可以为预防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.