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行实验证据表明，不同细胞类型(如巨噬细胞、脂肪细胞、脂肪细胞)细胞内胆固醇稳态的某些方面的破坏可导致2型糖尿病(T2 DM)之前的病理过程。我们最近对人类单核细胞(N=1,264)的转录研究证实了这些发现，这项研究特别确定了与T2 DM相关的基因的共表达胆固醇代谢网络(CMN)(趋势：5.07x10-10)。这个网络包含11个与胆固醇代谢相关的功能耦合基因，上调胆固醇的吸收和合成，下调胆固醇的外流，这是一个预计会增加细胞内胆固醇的分子图谱。此外，我们的数据以及体外和体内数据表明， T2 DM的两个重要危险因素--肥胖和炎症，可能是通过这个网络的改变来调节的。此外，我们确定了几个可能调节CMN基因表达并与T2 DM相关的DNA甲基化位点。然而，将CMN的分子特征与T2 DM风险联系起来的这一推断的强度受到我们人类数据的横截面性质的限制。在这里，我们的目标是阐明CMN的分子特征与T2 DM发病之间的时间关系，并进一步研究单核细胞网络改变的预期功能后果如何与T2 DM的发展相关。我们假设，CMN的分子特征与胆固醇摄取和合成的上调以及胆固醇外流的下调和细胞内胆固醇含量的增加有关，将预测未来发生T2 DM的更高风险。如果得到证实，结果将为开发一种系统的方法来调节这种CMN，而不是单个基因，以优化T2 DM的预防和治疗提供理论基础。基于这些初步数据，并利用1,264个CD14+(主要是单核细胞)样本的现有基因组、DNA甲基组和转录数据的良好表型多种族动脉粥样硬化(MESA)队列，我们现在建议对额外的单核细胞样本(N=1,536)进行分析，跟踪评估T2D状态，并在体外表征单核细胞功能，以实现以下特定目标：1)在单核细胞样本中独立复制T2 DM与CMN(DNA甲基化和mRNA)分子特征的横断面关联；2)确定CMN的分子特征(DNA甲基化和信使核糖核酸)是否可以预测7年后T2 DM的发生；3)确定CMN改变所预测的细胞内代谢的差异是否可以预测T2 DM的发生。遗传、表观遗传、转录和临床数据的整合以及体外实验研究可能提供 关于细胞胆固醇代谢在易感性中的作用的新的机制见解 到T2 DM，可能导致新的预防或治疗策略。