Obesity-Related Epigenetic Changes and Type-2 Diabetes

肥胖相关的表观遗传变化和 2 型糖尿病

• 批准号: 9928648
• 负责人: YONGMEI LIU
• 金额: $ 43.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9928648
• 关键词: Age; Apolipoprotein A-I; Beta Cell; Bioinformatics; CD14 gene; Cells; Cholesterol; Cholesterol Homeostasis; Clinical Data; County; Coupled; Cryopreservation; DNA Methylation; Data; Development; Down-Regulation; Epigenetic Process; Equation; Ethnic Origin; Future; Gender; Genes; Genetic; Genetic Transcription; Genomic DNA; Goals; High Density Lipoproteins; Human; In Vitro; Individual; Inflammation; Lead; Link; Lipids; Logistic Regressions; Measures; Mediating; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Profiling; Molecular and Cellular Biology; Multi-Ethnic Study of Atherosclerosis; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Participant; Pathologic Processes; Phenotype; Predisposition; Prevention; Prevention strategy; Process; Prospective Studies; Protein Export Pathway; Relative Risks; Research; Risk; Risk Factors; Role; Sampling; Scientist; Signal Transduction; Site; Societies; Structure; Up-Regulation; Work; base; case control; cell type; cohort; cost; design; experience; experimental study; follow up assessment; follow-up; genetic epidemiology; genome-wide; high risk; human data; in vivo; insight; lipid biosynthesis; macrophage; methylomics; monocyte; non-diabetic; non-genetic; novel; protein B; public health relevance; transcriptomics; treatment strategy; uptake

 DESCRIPTION (provided by applicant): Several lines of experimental evidence, including our own work, indicate that disruption of certain aspects of intracellular cholesterol homeostasis in various cell types (e.g. macrophage, ¿-cell, adipoctyes) can lead to pathological processes preceding Type 2 diabetes mellitus (T2DM). Our recent transcriptomic study of human monocytes (N=1,264) corroborates these findings, and this study specifically identified a co-expressed cholesterol metabolism network (CMN) of genes whose alterations were associated with T2DM (ptrend: 5.07x10- 10). This network contained 11 functionally coupled genes related to cholesterol metabolism, with up-regulation of cholesterol uptake and synthesis, and down-regulation of cholesterol efflux a molecular profile expected to increase intracellular cholesterol. Furthermore, our data along with in vitro and in vivo data suggest that the effects of two important risk factors for T2DM - obesity and inflammation, may be mediated through alterations in this network. In addition, we identified several DNA methylation sites that potentially regulate expression of the CMN genes and were associated with T2DM. However, the strength of this inference linking the molecular features of CMN toT2DM risk is limited by the cross-sectional nature of our human data. Here our goal is to elucidate the temporal relationship between molecular features of the CMN and T2DM onset and to further investigate how the predicted functional consequences of the altered network in monocytes relate to the development of T2DM. We hypothesize that the molecular features of the CMN related to up-regulation of cholesterol uptake and synthesis and down-regulation of cholesterol efflux and increase in intracellular cholesterol content will predict a higher risk for developing future T2DM If confirmed, results will provide a rationale for developing a systematic approach to modulate this CMN, rather than individual genes, for optimizing the prevention and treatment of T2DM. Based on these preliminary data, and taking advantage of the well-phenotyped Multi-Ethnic Study of Atherosclerosis (MESA) cohort with existing genomic, DNA methylomic, and transcriptomic data on 1,264 CD14+ (primarily monocyte) samples, we now propose to carry out analyses of additional monocyte samples (N=1,536), a follow-up assessment of T2D status, and in vitro characterization of monocyte functions to achieve the following specific aims: 1) To independently replicate cross-sectional associations of T2DM with the molecular features of CMN (DNA methylation and mRNA) in monocyte samples; 2) To determine whether the molecular features of CMN (DNA methylation and mRNA) can predict incident T2DM in a 7-year follow-up; and 3) To determine whether differences in intracellular metabolism which would be predicted from the CMN alterations can predict incident T2DM. The integration of genetic, epigenetic, transcriptional, and clinical data along with in vitro experimental studies may provide novel mechanistic insights concerning the role of cellular cholesterol metabolism in susceptibility to T2DM, possibly leading to new prevention or treatment strategies.

 描述（由申请人提供）：包括我们自己的工作在内的几条实验证据表明，各种细胞类型（例如巨噬细胞、¿细胞、脂肪细胞）中细胞内胆固醇稳态的某些方面的破坏可能导致 2 型之前的病理过程我们最近对人类单核细胞 (N=1,264) 的转录组学研究证实了这些发现，并且这项研究特别确定了一个其改变与 T2DM 相关的基因的共表达胆固醇代谢网络 (CMN)（ptrend：5.07x10-10）该网络包含 11 个与胆固醇代谢相关的功能耦合基因，胆固醇摄取和合成的上调和下调。 -胆固醇流出的分子特征预计会增加细胞内胆固醇此外，我们的数据以及体外和体内数据表明，的影响。 T2DM 的两个重要危险因素——肥胖和炎症，可能是通过该网络的改变介导的。此外，我们还发现了几个可能调节 CMN 基因表达并与 T2DM 相关的 DNA 甲基化位点。将 CMN 的分子特征与 T2DM 风险联系起来受到人类数据的横截面性质的限制，我们的目标是阐明 CMN 和 T2DM 发病的分子特征之间的时间关系，并进一步研究预测的结果。我们发现，单核细胞网络改变的功能后果与 T2DM 的发展有关，CMN 的分子特征与胆固醇摄取和合成的上调以及胆固醇流出的下调和细胞内胆固醇含量的增加有关。如果得到证实，结果将为开发一种系统方法来调节这种 CMN 而不是单个基因提供依据，以根据这些初步数据优化 T2DM 的预防和治疗。表型良好的动脉粥样硬化多种族研究 (MESA) 队列具有 1,264 个 CD14+（主要是单核细胞）样本的现有基因组、DNA 甲基组学和转录组数据，我们现在建议对其他单核细胞样本 (N=1,536) 进行分析，对 T2D 状态进行后续评估，以及单核细胞功能的体外表征，以实现以下具体目标：1）独立复制单核细胞样本中具有 CMN（DNA 甲基化和 mRNA）分子特征的 T2DM；2) 确定 CMN（DNA 甲基化和 mRNA）分子特征是否可以在 7 年随访中预测 T2DM 的发生；确定从 CMN 改变预测的细胞内代谢差异是否可以预测发生的 T2DM 遗传、表观遗传、转录和临床数据以及体外实验研究的整合可以提供。 关于细胞胆固醇代谢在易感性中的作用的新机制见解 T2DM，可能会导致新的预防或治疗策略。