Identifying the Immunoepigenetic Signature of Type 2 Diabetes

识别 2 型糖尿病的免疫表观遗传学特征

• 批准号: 9211069
• 负责人: Michael Jay Corley
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9211069
• 关键词: Address; Affect; Behavior; Biological Assay; Cells; Centers of Research Excellence; Chronic; Clinical; Collaborations; Communities; Cross-Sectional Studies; DNA; DNA Methylation; DNA sequencing; Data; Databases; Development; Diabetes Mellitus; Diet; Economic Conditions; Environment; Environmental Risk Factor; Epigenetic Process; Flow Cytometry; Gene Expression; Genes; Genetic Transcription; Glucose; Goals; Health; Healthcare; High Fat Diet; High Prevalence; Human Genome; Immune; Immune system; Immunologics; Individual; Inflammation; Inflammatory; Inflammatory Response; Instruction; Insulin; Intervention; Ions; Knowledge; Link; Lipopolysaccharides; Massive Parallel Sequencing; Measures; Messenger RNA; Methods; Methylation; Molecular; Native Hawaiian; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Pacific Island Americans; Participant; Patients; Pattern; Physiology; Population; Prevalence; Quantitative Reverse Transcriptase PCR; RNA; RNA Splicing; Recruitment Activity; Research; Research Personnel; Research Technics; Self Management; Semiconductors; Site; Social Conditions; Stimulus; Syndrome; Technology; Testing; base; bead chip; bisulfite sequencing; cytokine; diabetic; diagnostic assay; differential expression; early onset; epigenetic regulation; epigenome; epigenomics; experience; genome-wide; glycemic control; health disparity; immunoregulation; improved; insulin sensitivity; mRNA Precursor; macrophage; methylation pattern; methylome; molecular diagnostics; monocyte; non-diabetic; novel; novel strategies; obesogenic; response; sedentary lifestyle; sequencing platform; transcriptome; transcriptome sequencing

Project Summary/Abstract Type-2 diabetes (DM) disproportionately affects Native Hawaiians (NHs) compared with the general U.S. population. Under an obesogenic environment (i.e. high-fat diet, sedentary lifestyle and other behaviors associated with obesity), immune inflammation precedes and contributes to the development and progression of DM. What remain unclear are the molecular mechanisms by which specific immune cells modify their inflammatory potential and associate with insulin sensitivity in DM. Identifying and characterizing epigenetic mechanisms involved in immune inflammation will be of significant importance in understanding the development, progression, and treatment of DM among health disparity populations. We have established collaborations with the NH community and DM researchers to recruit DM participants to characterize epigenetic mechanisms including DNA methylation in regulating monocyte cells inflammatory function in DM. Our preliminary data in NH participants' undergoing a DM intervention revealed participants' ex vivo monocyte inflammation response reduced when glycemic control improved. Moreover, the altered inflammation state of monocytes related to significant differences in DNA methylation and gene expression of proinflammatory genes. Based on our preliminary findings, our hypothesis is that the obesogenic environment leads to DM influences the DNA methylation landscape of monocytes, including at pro-inflammatory genes, which pre- conditions their inflammatory potential. This altered epigenetic state primes monocytes to over-respond to inflammatory stimuli, leading to chronic inflammation and increased insulin insensitivity in the diabetic state. We will test this hypothesis through the following Specific Aims: (1)Determine the relationship between monocyte inflammatory response and insulin sensitivity in diabetic and normal, non-diabetic participants from the NH community. Here we measure monocyte cells functional response to inflammatory stimuli by an ex vivo assay developed by our collaborator. (2)Measure and compare the DNA methylomes of monocytes from diabetic and normal, non-diabetic participants. We will use a methylation array to evaluate and compare genome-wide DNA methylation patterns from diabetic and normal, non-diabetic individuals monocytes at >850,000 CpG sites across the human genome. (3)Characterize and compare the transcriptomes of monocytes from diabetic and normal, non-diabetic participants. We will examine gene expression and pre- mRNA splicing genome-wide using RNA-Sequencing and determine the functional consequences of differential DNA methylation. Collectively, this unique clinical, immunological, and epigenomic database may enable the development of novel molecular diagnostic assays to inform patient-specific health care decisions to reduce DM-associated health outcomes in the NH/PI community.

项目摘要/摘要 与普通美国人相比，2型糖尿病(DM)对夏威夷原住民(NHS)的影响不成比例。 人口。在肥胖环境下(即高脂肪饮食、久坐的生活方式和其他行为 与肥胖有关)，免疫炎症先于并促进了疾病的发展和进展 对DM。目前尚不清楚的是，特定的免疫细胞通过哪些分子机制来改变它们的 糖尿病患者的炎症潜能及其与胰岛素敏感性的关系。表观遗传学的鉴定和表征 参与免疫炎症的机制对于理解 糖尿病在健康差距人群中的发展、进展和治疗。我们已经确立了 与NH社区和DM研究人员合作招募DM参与者以确定 包括DNA甲基化在内的表观遗传学机制在调节糖尿病单核细胞炎症功能中的作用。 我们对接受糖尿病干预的NH参与者的初步数据显示，参与者的体外单核细胞 当血糖控制改善时，炎症反应减少。此外，血管炎症状态的改变 单核细胞DNA甲基化与促炎基因表达的显著差异 基因。根据我们的初步发现，我们的假设是肥胖环境导致糖尿病 影响单核细胞的DNA甲基化格局，包括在促炎基因，这是前 调节他们的炎症潜在性。这种改变的表观遗传状态启动单核细胞对 炎症刺激，导致慢性炎症和糖尿病状态下胰岛素不敏感的增加。 我们将通过以下具体目标来检验这一假设：(1)确定 糖尿病和非糖尿病受试者单核细胞炎症反应和胰岛素敏感性 NH社区。在这里，我们通过体外实验测量单核细胞对炎性刺激的功能反应。 化验是由我们的合作者开发的。(2)单核细胞DNA甲基组的测定和比较 糖尿病和正常的、非糖尿病的参与者。我们将使用甲基化数组来评估和比较 糖尿病患者和非糖尿病患者单核细胞全基因组DNA甲基化模式 &gt；人类基因组中的850,000个CpG位点。(3)描述和比较 来自糖尿病患者和正常的非糖尿病患者的单核细胞。我们将研究基因的表达和前 使用RNA测序技术在全基因组范围内剪接mRNA并确定其功能后果 差异DNA甲基化。总的来说，这个独特的临床、免疫学和表观基因组数据库可以 支持开发新的分子诊断分析，为患者特定的医疗保健决策提供信息 以减少NH/PI社区中与DM相关的健康后果。