Epigenomic Conditioning of Monocyte Inflammatory Activity in Native Hawaiians with Diabetes

夏威夷原住民糖尿病患者单核细胞炎症活动的表观基因组调节

• 批准号: 10000972
• 负责人: Alika Keolaokalani Maunakea
• 金额: $ 7.78万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000972
• 关键词: Acute; Address; Age; Antigen Presentation; Bioinformatics; Biological Assay; Biological Markers; C-reactive protein; Cells; Characteristics; Chronic; Coupled; Cryopreservation; DNA; DNA Methylation; Data; Diabetes Mellitus; Diagnosis; Epidemiology; Epigenetic Process; Ethnic group; Etiology; Exhibits; Foundations; Future; Genes; Genetic Transcription; Goals; Health; Heterogeneity; High Prevalence; Homeostasis; Hypermethylation; IL8 gene; Immune; Immunology; Immunoprecipitation; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-1; Interleukin-6; Ligands; Lipopolysaccharides; Massive Parallel Sequencing; Measures; Methods; Modeling; Molecular; Native Hawaiian; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Pacific Island Americans; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Pilot Projects; Plasma; Play; Positioning Attribute; Prevalence; Production; Prospective Studies; RNA; Reporting; Research; Research Personnel; Risk Factors; Role; Sampling; Socioeconomic Factors; Source; TNF gene; Technology; Testing; Toll-like receptors; Training; Work; bead chip; bisulfite sequencing; cell type; cohort; conditioning; cytokine; data integration; early onset; epigenomics; experience; genome-wide; genomic locus; health disparity; immune function; lifestyle factors; methylome; methylomics; monocyte; multidisciplinary; non-diabetic; pathogen; prospective; racial and ethnic; sex

PROJECT SUMMARY/ABSTRACT A primary goal of this application is to understand the molecular basis of environmental and epigenetic interactions that consequently influence inflammatory states underlying Type-2 diabetes mellitus (DM). Native Hawaiians and Pacific Islanders (NHs/PIs) experience a disproportionately higher prevalence and earlier onset of DM than other ethnic groups. The socioeconomic and lifestyle factors conferring NHs/PIs to the heightened prevalence of DM associate with altered global levels of DNA methylation, an epigenetic mechanism likely to play a major role in regulating the chronic low-grade systemic inflammation characteristic of DM. Indeed, inflammation has been shown to be associated with global DNA hypermethylation in peripheral blood mononuclear cells (PBMCs), independent of other risk factors for DM. Interestingly, differential DNA methylation at specific genomic loci in PBMCs exhibited changes at genes related to immune function and inflammatory pathways, which are associated with biomarkers of inflammation. However, the heterogeneity in cell type composition of PBMCs makes it difficult to determine how these observed differences in DNA methylation associate with inflammation. Monocytes play a central role in both acute and chronic inflammation, secreting various pro-inflammatory cytokines after stimulation with toll like receptor ligands, and are thus a major source of systemic inflammation. DNA methylation regulates the transcriptional levels of pro- inflammatory cytokines expressed by monocytes. Together, these studies suggest that the DNA methylation landscape of monocytes may be associated with inflammatory states of the cells, which may be altered in DM to correspond with inflammation. We seek to examine this relationship in NHs/PIs, which has never before been reported. We have collected preliminary data that form the basis for the hypothesis that compared to healthy individuals, monocytes from NHs/PIs diagnosed with DM exhibit a distinct DNA methylomic landscape, which conditions their heightened inflammatory response. To address this hypothesis, we propose to access our Multiethnic Cohort (MEC), from which we have detailed health information, and banked viably cryopreserved PBMCs and paired plasma biospecimens. We aim to (1) evaluate the relationships between insulin resistance, systemic inflammation, and ex vivo monocyte inflammatory activity in age- and sex-matched healthy (n=20) and DM-diagnosed (n=20) NHs/PIs, and (2) characterize and compare the DNA methylomes of these monocytes, following enrichment from PBMCs, using two independent yet complementary genome-wide approaches. We anticipate that these results will inform the extent to which the DNA methylomic landscape may condition monocyte inflammatory activity and how this associates with known risk factors for DM. This study will form the foundation for future work investigating the extent to which differences in monocyte function may be attributed to variability in DNA methylation between 5 distinct racial/ethnic groups in our MEC. Such studies would transform DM health disparities research to elucidate an epigenetic etiology.

项目摘要/摘要 该应用的主要目标是了解环境和表观遗传学的分子基础 因此影响2型糖尿病（DM）的炎症状态的相互作用。本国的 夏威夷人和太平洋岛民（NHS/PIS）经历的患病率不成比例，并且早期发作 与其他种族相比，DM的属于。社会经济和生活方式因素赋予NHS/PI的增长 DM与全球DNA甲基化水平改变的患病率，这是一种表观遗传机制 在调节DM的慢性低度系统炎症特征方面起着重要作用。的确， 炎症已显示与外周血中的全局DNA高甲基化有关 单核细胞（PBMC），与DM的其他风险因素无关。有趣的是，差异DNA PBMC中特定基因组基因局的甲基化在与免疫功能和 炎症途径与炎症的生物标志物有关。但是，异质性 PBMC的细胞类型组成使难以确定这些观察到的DNA差异 甲基化与炎症相关。单核细胞在急性和慢性炎症中都起着核心作用， 用像受体配体刺激刺激后，分泌各种促炎性细胞因子，因此是一个 全身炎症的主要来源。 DNA甲基化调节了促值的转录水平 单核细胞表达的炎性细胞因子。总之，这些研究表明DNA甲基化 单核细胞的景观可能与细胞的炎症状态有关，在DM中可能会改变 与炎症相对应。我们试图在NHS/PIS中检查这种关系，这种关系从来没有 报道了。我们收集了初步数据，这构成了与 健康个体，诊断为DM的NHS/PI的单核细胞表现出独特的DNA甲基甲基景观， 这构成了他们炎症反应的增强。为了解决这一假设，我们建议访问 我们的多民族队列（MEC），我们从中获得了详细的健康信息，并依靠 冷冻保存的PBMC和配对的等离子体生物测量。我们的目标是（1）评估 年龄和性别匹配的胰岛素抵抗，全身性炎症和离体单核细胞炎症活动 健康（n = 20）和DM诊断（n = 20）NHS/PI，（2）表征并比较 这些单核细胞在PBMC富集之后使用两个独立但互补的基因组的单核细胞 方法。我们预计这些结果将告知DNA甲基团景观的程度 可能会调节单核细胞炎症活性以及该如何与DM的已知风险因素相关联。这 研究将构成未来工作的基础，研究单核细胞功能差异的程度 可能归因于我们MEC中5种不同种族/种族之间DNA甲基化的变异性。这样的 研究将改变DM健康差异研究以阐明表观遗传学的病因。