Epigenetic changes and methylglyoxal adducts induced by metabolic regulation in patients with type 1 diabetes that develop complications

发生并发症的 1 型糖尿病患者代谢调节诱导的表观遗传变化和甲基乙二醛加合物

• 批准号: 10264144
• 负责人: Sarah C. Shuck
• 金额: $ 22万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10264144
• 关键词: Acetylation; Age; Blood; Cardiovascular Diseases; Cause of Death; Clinical Research; Complication; Complications of Diabetes Mellitus; DNA; DNA Methylation; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Progression; Enrollment; Epidemiology; Epigenetic Process; Etiology; Follow-Up Studies; Foundations; Future; Gene-Modified; Genes; Glycolysis; Glycosylated hemoglobin A; Goals; Histones; Incidence; Inflammation; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Kidney Diseases; Knowledge; Lead; Lipolysis; Literature; Lysine; Measures; Memory; Metabolic; Metabolic Marker; Modification; Molecular; Monitor; Outcome; Participant; Pathway interactions; Patients; Play; Population; Preventive therapy; Production; Proteins; Proteolysis; Pyruvaldehyde; RNA; Regulation; Research Personnel; Resources; Retinal Diseases; Role; Sampling; Source; Time; Urine; Work; adduct; arm; case control; cohort; conventional therapy; diabetes control; epigenetic marker; glycemic control; macrovascular disease; metabolic abnormality assessment; mortality; new therapeutic target; novel; novel marker; predictive marker; predictive modeling; predictive tools; prevent; sex; therapeutic target; tool; treatment arm

Abstract. The incidence of type 1 diabetes (T1D) has increased as much as 3-4% annually in recent decades. Furthermore, patients with T1D are vulnerable to developing micro- and macrovascular complications, the leading cause of death in this population. To reduce mortality in patients with T1D, there is a critical need to identify susceptible populations prior to the onset of complications so that preventative therapies can be implemented. To do this, we must identify the specific cellular factors involved in disease etiology. A promising source of these mediatory cellular factors is poor glycemic control, which is significantly associated with complications. To identify and characterize these factors, we, along with our Co-Investigator Dr. Rama Natarajan, have accessed samples from an established, longitudinal clinical study investigating the role of glycemic control on complication progression. Analysis of samples collected pre-complication development revealed specific metabolites and epigenetic signatures associated with poor glycemic control; we hypothesize that these may have utility as predictive biomarkers of complications and will explore this in Aim 1. Analysis of samples collected post-complication development revealed that these same metabolic and epigenetic markers remained elevated over time, even after strong glycemic control was established. We hypothesize that these markers are indicative of long-term poor glycemic control and will explore this in Aim 2. Our goals for Aims 1 and 2 are to build a predictive model for complications and determine the extent to which metabolic and epigenetic markers are associated with poor glycemic control. Beyond the utility of metabolic and epigenetic markers for predicting and monitoring disease progression, we discovered that they influence specific cellular pathways such as glycolysis, lipolysis, proteolysis, and inflammation. We hypothesize that interrelated components of these pathways play a role in complication etiology and will explore this in Aim 3. Our goal in Aim 3 is to establish the foundational information to explore the role of specific pathway components in complication etiology and progression. The work in this proposal is the first example of combined analysis of metabolic and epigenetic markers in complication etiology.

抽象的。 近几十年来，1型糖尿病（T1D）的发生率每年增加3-4％。此外， T1D患者容易发生微血管并发症，这是 该人群的死亡。为了降低T1D患者的死亡率，迫切需要确定易感性 并发症发作之前的种群，以便可以实施预防性疗法。为此， 我们必须确定疾病病因涉及的特定细胞因素。这些调解的有前途的来源 细胞因子是血糖控制差，这与并发症显着相关。识别和 特征这些因素，我们以及我们的共同研究员Rama Natarajan博士都从 一项已建立的纵向临床研究，研究了血糖控制对并发症进展的作用。 分析收集的预补贴开发的样品揭示了特定的代谢物和表观遗传学 与血糖控制不良有关的特征；我们假设这些可能具有预测性 并发症的生物标志物，并将在AIM 1中探索这一点。对复杂后收集的样品的分析 发展表明，随着时间的流逝，这些相同的代谢和表观遗传标志物仍然升高 建立强血糖控制后。我们假设这些标记表明长期 血糖控制不良，并将在目标2中探索这一点。我们的目标1和2是建立一个预测模型 对于并发症，并确定代谢和表观遗传标记与较差有关的程度 血糖控制。除了代谢和表观遗传标记的效用以预测和监测疾病 进展，我们发现它们会影响特定的细胞途径，例如糖酵解，脂解， 蛋白水解和炎症。我们假设这些途径的相互关联的组成部分在 并发症病因并将在AIM 3中探讨这一点。我们的目标3是建立基础信息 探索特定途径成分在并发症病因和进展中的作用。这项工作 建议是并发症病因中代谢和表观遗传标记的组合分析的第一个例子。