Single-cell epigenomics and transcriptomics of diabetic gastroparesis in humans

人类糖尿病胃轻瘫的单细胞表观基因组学和转录组学

• 批准号: 10360731
• 负责人: ADIL E. BHARUCHA
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10360731
• 关键词: Address; Affect; Autonomic nervous system; Behavior; Biopsy; Cells; Chromatin; Chronic; Collaborations; Complement; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Disease; Distress; Duodenum; Endocrine; Enteral; Epigenetic Process; Functional disorder; Future; Gastrectomy; Gastric Emptying; Gastroparesis; Gene Expression; Genes; Growth Factor; Harvest; Histologic; Human; Hyperglycemia; IGF1 gene; Immune; Immunity; Immunophenotyping; Impairment; Inflammatory; Interstitial Cell of Cajal; Leukocytes; Link; Metabolic; Mission; Mitochondria; Molecular; Mus; Muscle; Natural Immunity; Neurons; Nuclear; Organ; Oxidative Stress; PTPRC gene; Pathogenesis; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Proteomics; Role; Signal Pathway; Smooth Muscle; Stomach; Symptoms; Thick; Tissues; Upper digestive tract structure; base; bench to bedside; cell type; design; diabetic; diabetic gastroparesis; epigenome; epigenomics; experimental study; gastrointestinal symptom; genome-wide; glycemic control; histone modification; improved; in vivo; ineffective therapies; inflammatory milieu; insulin signaling; mitochondrial dysfunction; nitrosative stress; nonulcer dyspepsia; novel marker; prevent; repository; transcriptome; transcriptome sequencing; transcriptomics

PROJECT SUMMARY/ABSTRACT Similar to other complications of diabetes mellitus (DM), diabetic gastroenteropathy (DGE) reflects organ- specific dysfunctions likely due to DM-related endocrine, metabolic and immune/inflammatory disturbances. Therapies for DGE are ineffective and address the symptoms, not the disease itself. Hence, and aligned with the mission of RFA-DK-20-030, this proposal seeks to uncover the cellular and molecular mechanisms of DGp and its relative, non-ulcer dyspepsia, in carefully phenotyped patients. We focus on the links between dysimmunity, ICC, glycemia, and mitochondrial dysfunction. The specific aims are as follows: Aim 1. To analyze the relationship between the transcriptome and epigenome of single gastric immune cells, gastric emptying (GE), and glycemia in DM and non-DM patients with upper GI symptoms. Aim 2. To determine the relationship between the transcriptome and epigenome of single circulating PBMCs and single gastric immune cells in DM and non-DM patients with upper GI symptoms. Aim 3. To investigate the relationship between the transcriptome and epigenome of single gastric ICC and immune cells and single circulating PBMCs in DM and non-DM patients with upper GI symptoms. These studies will be investigated with in vivo (i.e., assessment of the DM phenotype, gastrointestinal symptoms, and GE) followed by ex vivo assessments (i.e., transcriptome and epigenome of single circulating PBMCs, single gastric CD45+ cells, and single ICC) in 45 patients undergoing sleeve gastrectomy (i.e., 15 patients in each of 3 groups: non-DM + normal GE, DM + normal GE, DM + delayed GE). This proposal is anchored by, and builds on, an established bench-to-bedside collaboration between Drs. Bharucha and Ordog which, through their complementary expertise, has enhanced our understanding of diabetic gastroparesis. It seeks to better understand the pathogenesis, and through the studies in peripheral immune cells also identify novel biomarkers, of DGE.

项目总结/摘要 与糖尿病（DM）的其他并发症相似，糖尿病胃肠病（DGE）反映了器官- 可能由于DM相关的内分泌、代谢和免疫/炎症紊乱引起的特定功能障碍。 DGE的治疗是无效的，只能解决症状，而不是疾病本身。因此，并与 RFA-DK-20-030的使命，该提案旨在揭示DGp的细胞和分子机制 及其相关的非溃疡性消化不良。我们关注的是 免疫异常、ICC、线粒体功能障碍。 具体目标如下：目标1。为了分析转录组与 DM和非DM患者单个胃免疫细胞表观基因组、胃排空（GE）和胃排空 上消化道症状目标2.为了确定转录组和表观基因组之间的关系， 糖尿病和非糖尿病上消化道症状患者的单个循环PBMC和单个胃免疫细胞。 目标3.探讨单个胃ICC的转录组和表观基因组的关系， 免疫细胞和单个循环PBMC在糖尿病和非糖尿病患者上消化道症状。 这些研究将在体内进行研究（即，DM表型评估，胃肠道 症状和GE），然后进行离体评估（即，转录组和表观基因组 PBMC，单个胃CD 45+细胞和单个ICC）在45例接受袖状胃切除术（即，15 非DM+正常GE组、DM +正常GE组、DM +延迟GE组各30例。这项建议是 Bharucha博士和Ordog博士之间建立了一个从实验室到床边的合作， 通过他们互补的专业知识，增强了我们对糖尿病胃轻瘫的理解。它 旨在更好地了解发病机制，并通过对外周免疫细胞的研究也确定 DGE的新生物标志物。