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（由适用提供）：糖尿病控制和并发症试验（DCCT）清楚地表明，严重的血糖控制会大大降低1型糖尿病患者（T1D）患者血管并发症的进展。在随后的糖尿病干预和并发症（EDIC）观察性研究的流行病学中，常规（CORS）和强化治疗（INT）DCCT组都转移到INT。出乎意料的是，前Cons组继续以明显高于先前的INT组的速率发展微血管并发症。这个称为“代谢记忆”的概念一直是T1D领域的主要谜。最近的证据表明，诸如染色质组蛋白修饰（PTM）之类的表观遗传因素调节与糖尿病并发症和代谢记忆相关的基因。然而，尚不清楚表观遗传标记（例如DNA甲基化（DNA-ME））在人类T1D并发症的进展和代谢记忆中的作用，我们建议在当前建议中解决这一主要知识。基于我们最近发表的数据，显示了来自EDIC队列的60名患者的关键组蛋白PTM的改变以及新的初步DNA-ME数据，我们的目标是现在探索较大的DCCT患者组中有价值的归档基因组DNA的糖尿病并发性与DNA-ME相关的机制。这些样品将与EDIC合作从其中央生物化学实验室合作，其中已从DCCT Close（1991-1993）的几乎所有DCCT参与者存档了基因组DNA。此外，我们最近与EDIC队列患者的研究已经产生的数据还将与本提案中生成的新数据集成。将评估四个具体目标，以检验中心假设，即DCCT期间关键易感基因组区域的高血糖引起的持续性表观遗传变化（DNA-ME和组蛋白PTM）会导致对DCCT CORV conver the Int Convers the Int ther ther ther ther the the the dcct中更持久并发症的代谢记忆。这些研究的结果可以帮助建立表观遗传学，并发症进展和潜在的人类代谢记忆之间的更牢固的关联。该提议既及时又是意义的，因为人类的表观基因组学处于医学研究的最前沿，但是在人类糖尿病并发症领域并不知道很多。这些仅使用归档材料的研究可以通过促进我们对尽管控制血糖的发展进展为基础的关键表观基因机制的理解来产生重大影响。反过来，这可以确定改善早期血糖控制是否可以预防高血糖诱发的表观遗传学变化，从而导致更新，更有效的治疗干预措施。这些创新的研究共同解决了T1D领域的关键科学差距和临床需求及其并发症，这是该NIDDK DP3计划的目标。