Novel Paradigms in Diabetic Complications

糖尿病并发症的新范例

• 批准号: 8241583
• 负责人: Kumar Sharma
• 金额: $ 595.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8241583
• 关键词: 18 year old; Albumins; Animal Model; Animals; Automobile Driving; Biochemical; Biogenesis; Biological Markers; Calories; Cell Culture Techniques; Cells; Child; Chronic Kidney Failure; Complications of Diabetes Mellitus; Creatinine; Data; Developed Countries; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Electron Transport; Epigenetic Process; Event; Excess Mortality; Exposure to; Functional disorder; Future; Genome; Glomerular Filtration Rate; Glucose; Human; Hyperglycemia; Image; Imaging Device; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Lead; Life; Link; Mediating; Mediator of activation protein; Medical; Metabolism; Methylation; Mitochondria; Modeling; Modification; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Population; Process; Production; Protocols documentation; Public Health; Renal function; Risk Factors; Role; Sampling; Series; Stimulation of Cell Proliferation; Structure; Superoxides; System; Systems Biology; Testing; Tissues; Urine; Work; base; cohort; diabetic; epigenomics; follow-up; human subject; kidney cell; metabolomics; mouse model; novel; promoter; response; theories; type I and type II diabetes

DESCRIPTION (provided by applicant): Diabetic kidney disease is recognized as the leading cause of excess mortality in the population with type 1 diabetes. The prevailing theory is that excess calories are processed via the mitochondria resulting in accumulation of superoxide radicals via the electron transfer chain. However, our exciting data generated from live animal imaging demonstrates a completely opposite set of conclusions. There is actually a dramatic reduction of superoxide radicals in response to a high caloric state in tissues prone to diabetic complications. To determine if reduced mitochondrial function also occurs in humans, we evaluated the urine metabolome and found that patients with diabetes and kidney disease had reduced metabolites related to mitochondrial function. In the present proposal we will use two large well characterized cohorts of patients from the FinnDiane Study and the CRIC study to demonstrate the role of these urine metabolites in determining future renal disease. We will also identify if epigenetic modification of the PGC1a promoter may underlie the reduction in mitochondrial function in patients and in animal models. Using a systems biology and imaging approach we will link the reduction in mitochondrial function with alterations in the metabolome and epigenome in the kidney and the urine. This application will be a paradigm shifting approach to the medical challenge of hyperglycemia induced kidney disease. PUBLIC HEALTH RELEVANCE: The renal complications of diabetes are perhaps the number one public health problem facing industrialized nations. By identifying the urine metabolome and epigenome in patients with type 1 diabetes and kidney disease we hope to gain a better understanding of the basis of kidney complications of type 1 diabetes.

描述（由申请人提供）：糖尿病肾病被认为是1型糖尿病人群死亡率过高的主要原因。流行的理论是过量的卡路里通过线粒体处理，导致超氧自由基通过电子转移链积累。然而，我们从活体动物成像中获得的令人兴奋的数据表明了一组完全相反的结论。事实上，在易于发生糖尿病并发症的组织中，超氧自由基在高热量状态下会急剧减少。为了确定线粒体功能降低是否也发生在人类中，我们评估了尿液代谢组，发现糖尿病和肾脏疾病患者与线粒体功能相关的代谢物减少。在本提案中，我们将使用来自FinnDiane研究和CRIC研究的两个大的充分表征的患者队列来证明这些尿液代谢物在确定未来肾脏疾病中的作用。我们还将确定PGC1a启动子的表观遗传修饰是否可能是患者和动物模型中线粒体功能降低的基础。使用系统生物学和成像方法，我们将把线粒体功能的减少与肾脏和尿液中代谢组和表观基因组的改变联系起来。这一应用将是一种范式转变的方法，以应对高血糖症引起的肾脏疾病的医学挑战。 公共卫生相关性：糖尿病的肾脏并发症可能是工业化国家面临的头号公共卫生问题。通过鉴定1型糖尿病和肾脏疾病患者的尿液代谢组和表观基因组，我们希望更好地了解1型糖尿病肾脏并发症的基础。