Mitochondrial and Oxidative Stress in Type 1 Diabetes

1 型糖尿病中的线粒体和氧化应激

• 批准号: 7229930
• 负责人: S. Michael Mauer
• 金额: $ 12.35万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7229930
• 关键词: Age; Antioxidants; Basic Science; Behavior; Behavioral; Biogenesis; Biological Markers; Cell physiology; Cells; Complication; Control Groups; Cross-Sectional Studies; Data; Development; Diabetic Nephropathy; Environment; Excision; Exposure to; Family history of; Fibroblasts; Gender; Gene Expression; Genes; Glucose; Grouping; Hyperglycemia; In Vitro; Inherited; Insulin-Dependent Diabetes Mellitus; Kidney Failure; Kidney Transplantation; Lesion; Measures; Memory; Methods; Microalbuminuria; Mitochondria; Natural History; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Predisposition; Prevention; Production; Proteinuria; Rate; Reactive Oxygen Species; Recruitment Activity; Relative (related person); Research; Research Personnel; Risk; Sampling; Score; Skin; Surrogate Markers; Testing; Up-Regulation; design; disorder risk; in vivo; innovation; insight; interest; non-diabetic; programs; response

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.

描述（由申请人提供）：糖尿病性肾病（DN），1型糖尿病（T1DM）的主要并发症和肾衰竭的主要原因，在其大部分自然历史中都保持沉默。几条证据表明，线粒体（MT）功能的异常和氧化应激增加是DN发病机理的重要组成部分。皮肤成纤维细胞（SF）体外行为反映了DN风险。来自T1DM患者SF的微阵列基因表达数据显示出快速DN发育的患者MT途径的上调，通过增加的活性氧（ROS）产生与氧化应激相一致。此外，与正常对照相比，在没有并发症的T1DM PT中看到了相似的定向途径基因表达的增加，这些发现与与T1DM本身的发病机理或体外高血糖的体外细胞记忆相关的细胞过程一致。 R21的应用旨在进一步追求这些观察结果，代表了肾脏学家，糖尿病学家和生物统计学家之间对DN研究感兴趣的肾脏学家和生物统计学家之间的创新伙伴关系，以及在MT功能和氧化压力方面具有专业知识的基本生物化学家。此处概述的研究将测试ROS产生和去除的MT或胞质失衡的氧化应激是否在SF中显而易见，其快速与DN发育缓慢以及DN发育缓慢和正常对照的患者的SF是明显的。如果是这样，这将提供设计进一步研究所需的初步数据，以测试这些SF行为变量是否为：a）继承； b）依赖于SF事先暴露于T1DM； （c）存在于外周血单核细胞中，因此可以适应方便的疾病风险生物标志物。总而言之，这些研究可以提供DN和T1DM风险的准确和方便的替代标记，以及对DN和T1DM的致病见解，并可以为预防T1DM及其并发症提供新的治疗靶标。