Multimodal omics approach to identify health to cardiometabolic disease transitions

多模式组学方法确定健康状况向心脏代谢疾病的转变

• 批准号: 10753664
• 负责人: Paivi Pajukanta
• 金额: $ 70.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753664
• 关键词: ATAC-seq; Address; Adipocytes; Adipose tissue; Aorta; Automobile Driving; Biological; Biological Assay; Biological Markers; Biomedical Research; Body mass index; Cardiometabolic Disease; Caring; Cell Nucleus; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Deterioration; Diabetes Mellitus; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Fatty acid glycerol esters; Female; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Health; Health Transition; High Fat Diet; High Prevalence; Human; Individual; Inflammation; Inflammatory; Insulin Resistance; Knowledge; Ligands; Link; Lipids; Liver; Maps; Mediating; Medical; Mendelian randomization; Metabolic; Mexican; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Obesity; Obesity Epidemic; Overnutrition; Overweight; Phenotype; Population Heterogeneity; Prevention; Protein Secretion; Publishing; RNA Sequences; Regulatory Element; Reporter; Role; Running; Sampling; Serum; Sex Differences; Sex Factors; Site; Small Interfering RNA; Stimulus; TREM2 gene; Testing; Thinness; Time; Tissue Sample; Tissues; Variant; Visceral; Weight; biobank; candidate identification; cardiometabolism; cell type; cohort; disorder risk; epidemiology study; epigenomics; experience; follow-up; functional genomics; gene discovery; gene environment interaction; genetic linkage analysis; genome wide association study; genomic data; global health; inflammatory marker; lipid biosynthesis; male; multimodality; multiple omics; non-alcoholic fatty liver disease; personalized strategies; polygenic risk score; prevent; response; risk variant; sex; single nucleus RNA-sequencing; single-cell RNA sequencing; subcutaneous; trait; transcriptome sequencing; transcriptomics

Abstract: The global obesity epidemic drives the high prevalence of cardiometabolic disorders (CMDs), including type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). Epidemiological studies have also established strong sex differences in CMDs. Obesity-induced low-grade inflammation and insulin resistance in adipose tissue (AT), their deteriorating impacts on the efficacy of adipogenesis, and subsequent ectopic fat storage into other cardiometabolic tissues, particularly liver, have been proposed as the key drivers of the CMD risks related to obesity. However, the mechanisms promoting the transitions from health-to-disease states in human fat depots have remained largely elusive. We hypothesize that there are transcriptional inflammatory markers and cell-type-specific changes in open chromatin pertinent to health-to-CMD transitions that can be discovered using single cell level and bulk omics analyses in fat cell-types and tissue. We also hypothesize that by elucidating molecular responses to obesity-related stimuli during adipogenesis we can discover candidate variants and genes with functional priors for formal identification of gene-sex and gene-environment interactions (i.e. GxSs and GxEs) underlying obesity-induced health-to-CMD transitions in large biobanks. In Aim 1, we will generate sex- and context-specific bulk and single cell level transcriptomics (RNA-seq) and epigenomics (ATAC- seq) data in two obesity-relevant fat depots, i.e. subcutaneous and visceral AT, to identify epigenetic and transcriptional markers for health-to-CMD transitions in six health-to-CMD stages comprising lean, overweight, and obese males and females with and without prediabetes, T2D, and NAFLD. We will also use existing serum samples to discover health-to-CMD transition biomarkers among the genes that differ between the six health/disease states and encode secreted proteins. We will test the top results for replication in independent omics cohorts, including Mexicans. In Aim 2, we will use a new function-to-variants omics approach to discover GxSs and GxEs involved in early transitions from health to CMD in males and females. We will generate functional genomics data in CMD-relevant human primary preadipocytes, extracted from fresh AT of normal weight, metabolically healthy males and females. These preadipocytes will be differentiated with and without key inflammatory stimuli to discover stimuli-responsive adipogenesis genes and cis-regulatory elements (CREs) that harbor regulatory variants in diverse populations. Subsequently, these variants will be fine-mapped using massively parallel reporter assay in (pre)adipocytes and functionally characterized using extensive variant-to- gene-linkage analysis and genomic perturbations (CRISPR and siRNA). The identified candidate SNPs will be tested for GxE and GxS effects on health-to-CMD transitions in large biobanks to verify their role in these critical transitions. Our preliminary results and ample previous experience with integrative multiomics approaches of CMDs provide a strong prior scientific rigor for the proposed Aims, and overall, accomplishing our Aims has a great potential to develop personalized strategies that prevent or postpone the onset of obesity-related CMDs.

摘要：全球肥胖流行导致心脏代谢疾病（CMD）的高患病率， 包括 2 型糖尿病 (T2D) 和非酒精性脂肪肝 (NAFLD)。流行病学研究有 还建立了 CMD 的强烈性别差异。肥胖引起的低度炎症和胰岛素抵抗 在脂肪组织（AT）中，它们对脂肪生成功效的恶化影响以及随后的异位脂肪 储存到其他心脏代谢组织，特别是肝脏，已被认为是 CMD 的关键驱动因素 与肥胖有关的风险。然而，促进健康状态向疾病状态转变的机制 人类脂肪库在很大程度上仍然难以捉摸。我们假设存在转录炎症 开放染色质中与健康到 CMD 转变相关的标记和细胞类型特异性变化，可以 通过对脂肪细胞类型和组织进行单细胞水平和体组学分析发现了这一点。我们还假设 通过阐明脂肪生成过程中对肥胖相关刺激的分子反应，我们可以发现候选者 具有功能先验的变体和基因，用于正式鉴定基因-性别和基因-环境相互作用 （即 GxSs 和 GxEs）是大型生物库中肥胖引起的健康向 CMD 转变的基础。在目标 1 中，我们将 生成性别和环境特异性的批量和单细胞水平转录组学 (RNA-seq) 和表观基因组学 (ATAC- seq）两个与肥胖相关的脂肪库（即皮下和内脏 AT）的数据，以识别表观遗传和 六个健康到 CMD 阶段（包括瘦、超重、 患有或不患有糖尿病前期、T2D 和 NAFLD 的肥胖男性和女性。我们还将使用现有的血清 样本以发现六种不同基因之间从健康到 CMD 的转变生物标志物 健康/疾病状态并编码分泌蛋白。我们将测试独立复制的最佳结果 组学群体，包括墨西哥人。在目标 2 中，我们将使用一种新的功能到变异组学方法来发现 GxSs 和 GxEs 参与男性和女性从健康到 CMD 的早期转变。我们将生成 从正常人的新鲜 AT 中提取的 CMD 相关人原代前脂肪细胞的功能基因组学数据 体重、代谢健康的男性和女性。这些前脂肪细胞将在有或没有钥匙的情况下进行区分 炎症刺激以发现刺激反应性脂肪生成基因和顺式调节元件（CRE） 不同人群中存在调节变异。随后，这些变体将使用精细映射 在（前）脂肪细胞中进行大规模平行报告分析，并使用广泛的变体进行功能表征 基因连锁分析和基因组扰动（CRISPR 和 siRNA）。确定的候选 SNP 将是 在大型生物库中测试了 GxE 和 GxS 对健康到 CMD 转变的影响，以验证它们在这些关键中的作用 过渡。我们的初步结果和以前在综合多组学方法方面的丰富经验 CMD 为拟议的目标提供了强大的先验科学严谨性，总体而言，实现我们的目标有一个 开发预防或推迟肥胖相关 CMD 发作的个性化策略具有巨大潜力。