Epigenetic Markers of Complications and Metabolic Memory in the DCCT/EDIC cohort.

DCCT/EDIC 队列中并发症和代谢记忆的表观遗传标记。

• 批准号: 8970574
• 负责人: RAMA NATARAJAN
• 金额: $ 221.06万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8970574
• 关键词: Acetylation; Address; Archives; Biochemistry; Biological; Biological Markers; Blood Cells; Blood Vessels; Cardiovascular system; Chromatin; Clinical; Collaborations; Complication; Complications of Diabetes Mellitus; Control Groups; DNA; DNA Methylation; Data; Data Set; Diabetes Mellitus; Epidemiology; Epigenetic Process; Future; Gene Expression; Genes; Genetic; Genetic Databases; Genome; Genomic DNA; Glycosylated hemoglobin A; Goals; Histone H3; Histones; Human; Hyperglycemia; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Kidney Diseases; Knowledge; Laboratories; Lead; Lysine; Measures; Mediating; Medical Research; Memory; Metabolic; National Institute of Diabetes and Digestive and Kidney Diseases; Observational Study; Outcome; Participant; Pathology; Patients; Phase; Predisposition; Publishing; Recording of previous events; Reporting; Retinal Diseases; Risk; Role; Sample Size; Sampling; Testing; Therapeutic Intervention; Variant; base; case control; cohort; conventional therapy; data integration; diabetes control; effective therapy; epigenetic marker; epigenomics; experience; genome wide association study; genome-wide; glycemic control; histone modification; improved; innovation; macrovascular disease; novel; prevent; promoter; public health relevance

 DESCRIPTION (provided by applicant): The Diabetes Control and Complications Trial (DCCT) clearly demonstrated that tight glycemic control profoundly reduces the progression of vascular complications in patients with type 1 diabetes (T1D). In the subsequent Epidemiology of Diabetes Interventions and Complications (EDIC) observational study, both the conventional (CONV) and intensive treatment (INT) DCCT groups were shifted to INT. Surprisingly, the former CONV group continue to develop micro- and macrovascular complications at significantly greater rates than the previous INT group. This concept, called "metabolic memory", has been a major enigma in the field of T1D. Recent evidence suggests that epigenetic factors like chromatin histone modifications (PTMs) regulate genes associated with diabetic complications and metabolic memory. However, the role of epigenetic marks like DNA methylation (DNA-me) in human T1D complications progression and metabolic memory is not clear and we propose to address this major gap in knowledge in the current proposal. Based on our recently published data showing alterations in key histone PTMs in sixty patients from the EDIC cohort, as well as new preliminary DNA-me data, our objective is to now explore DNA-me associated mechanisms underlying diabetes complications progression using valuable archived genomic DNA from a bigger cohort of DCCT patients. These samples will be obtained in collaboration with EDIC from their Central Biochemistry laboratory where genomic DNA has been archived from nearly all the DCCT participants at DCCT closeout (1991-1993). In addition, data already generated from our recent study with EDIC cohort patients will also be used for integration with new data generated in this proposal. Four Specific Aims will be evaluated to test the Central Hypothesis that persistent epigenetic changes (DNA-me and histone PTMs) induced by hyperglycemia at key susceptible genome regions during the DCCT can lead to a metabolic memory of the more persistent complications noted during EDIC in the DCCT CONV cohort that was shifted from CONV to INT therapy. The results of these investigations can help establish firmer associations between epigenetics, complications progression and potentially human metabolic memory. This proposal is both timely and significant because human epigenomics is at the forefront of medical research and yet, not much is known in the field of human diabetic complications. These investigations, which use only archived material, can make a significant impact by advancing our understanding of key epigenetic mechanisms underlying the progression of T1D complications despite glycemic control. This, in turn, could determine whether improved early glycemic control can prevent hyperglycemia induced epigenetic changes, and thus lead to newer and more effective therapeutic interventions. Together, these innovative studies address a key scientific gap and clinical need in the field of T1D and its complications that are in line wth the goals of this NIDDK DP3 initiative.

 描述（由申请人证明）：糖尿病控制和汇编试验（DCCT）清楚地表明，紧密的紧密紧密紧密的Andoundl y降低了1型糖尿病的血管编译并发症的进度（T1D）。传统的（CORS）和强化治疗（INT）DCCT组转移到INT，以显着的速度比以前的INT组开发微血管汇编。 T1D。来自EDIC队列的六十名患者的关键组蛋白PTM的公开数据静脉以及新的Preliminare DNA-ME数据，我们的目标是使用较大的较大的基因组DNA的糖尿病基础汇编的DNA-ME相关机制，该机制来自更大的基因组DNA DCCT患者将从他们的中央生物化学中与EDIC合作。在此提案中使用的数据也可以与DCCT的主要易感基因组区域中的Y高血糖整合在一起研究可以帮助建立网络学之间的牢固的杂物，这是人类的代谢记忆。表观遗传机制尽管控制了T1D组成的进展这项NIDDK DP3倡议的目标是排队。