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: 10687103
• 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/10687103
• 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; 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.

项目摘要/摘要 与糖尿病（DM）的其他并发症相似，糖尿病性胃肠病（DGE）反映了器官 特定功能障碍可能是由于DM相关的内分泌，代谢和免疫/炎症性障碍引起的。 DGE的疗法无效，可以解决症状，而不是疾病本身。因此，与 RFA-DK-20-030的使命，该提案旨在发现DGP的细胞和分子机制 及其相对的非脉络性消化不良，在精心表现的患者中。我们专注于之间的联系 功能障碍，ICC，血糖和线粒体功能障碍。 具体目的如下：目的1。分析转录组与 DM和非DM患者的单胃免疫细胞，胃排空（GE）和糖血症的表观基因组 具有上胃肠道症状。目标2。确定转录组和表观基因组之间的关系 DM和非DM患者的单个循环PBMC和单胃免疫细胞。 目的3。调查单个胃ICC的转录组和表观基因组之间的关系 DM和非DM患者的免疫细胞和单个循环PBMC患者具有上GI症状。 这些研究将通过体内研究（即，DM表型的评估，胃肠道评估 症状，GE），然后进行离体评估（即单个循环的转录组和表观基因组 45例接受袖子胃切除术的患者中的PBMC，单胃CD45+细胞和单个ICC）（即15例 3组中的每一个患者：非DM +正常GE，DM +正常GE，DM +延迟GE）。该提议是 由DRS之间的既定基础与床位的合作建立并建立在基础上。 Bharucha和Ordog 通过他们的互补专业知识，这增进了我们对糖尿病性胃轻瘫的理解。它 试图更好地理解发病机理，并通过对周围免疫细胞的研究也确定 DGE的新型生物标志物。