Enteroendocrine Regulation of Intestinal Metabolism

肠道代谢的肠内分泌调节

• 批准号: 10301046
• 负责人: Heather A McCauley
• 金额: $ 12.7万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301046
• 关键词: 5' -AMP-activated protein kinase; Affect; Biochemistry; Biological Assay; Biological Models; Brain; Carbon Dioxide; Cell Communication; Cell Line; Cells; Communities; Community Physician; Coupled; Data; Development; Developmental Biology; Diarrhea; Dietary intake; Digestion; Digestive System Disorders; Distress; Electrophysiology (science); Endocrinology; Ensure; Enterocytes; Enteroendocrine Cell; Environment; Epithelial; Epithelial Cells; Exhibits; FRAP1 gene; Fluorescence; G-Protein-Coupled Receptors; Gastroenterology; Genetic Transcription; Genus Hippocampus; Goals; Health; Home; Hormones; Human; Hunger; Image; Individual; Ingestion; Institution; International; Intestines; Ions; Link; Mass Spectrum Analysis; Measures; Medical center; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mus; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nausea and Vomiting; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; Organoids; Pancreas; Paneth Cells; Parenteral Nutrition; Pathway interactions; Pediatric Hospitals; Pediatric Research; Peptide Signal Sequences; Peptides; Pharmacology; Physiology; Play; Pluripotent Stem Cells; Production; Protein Kinase; Public Health; Receptor Cell; Regenerative capacity; Regulation; Reporter; Research; Research Personnel; Respiration; Role; Satiation; Schedule; Scientist; Second Messenger Systems; Signal Transduction; Small Intestines; System; Testing; Time; Tissues; Training; United States; United States National Institutes of Health; Work; base; blood glucose regulation; cell motility; cell type; detection of nutrient; dietary; experimental study; gastrointestinal; gut health; hormonal signals; human model; innovation; insulin secretion; intestinal epithelium; intestinal homeostasis; metabolic rate; metabolomics; mouse model; novel; novel therapeutics; nutrient absorption; nutrition; paracrine; response; single cell analysis; single-cell RNA sequencing; stem cell niche; stem cells; success; training opportunity; transcription factor; uptake

PROJECT SUMMARY Dr. Heather McCauley is mentored by Dr. James Wells at Cincinnati Children’s Hospital Medical Center (CCHMC), the largest pediatric research institution in the nation. CCHMC ranked 2nd in NIH support in 2017 and is home to an NIDDK-sponsored Digestive Diseases Research Center with a vibrant community of physicians and scientists. CCHMC provides a very supportive training environment for young investigators. Dr. McCauley proposes an innovative cross-disciplinary research plan which bridges developmental biology, stem cell and organoid medicine, gastroenterology and nutrition, endocrinology, and metabolism. Enteroendocrine cells (EECs) are specialized intestinal epithelial cells which secrete more than 20 bioactive peptides to regulate satiety, gut motility, glucose homeostasis, nutrient absorption, and whole-body metabolism in response to ingested nutrients. While the systemic targets of EEC hormones are well known, such as the brain and the pancreas, the role of EEC peptides in regulating the function of the intestine itself is surprisingly understudied. Our lab has developed a unique, high-throughput human model system to test the roles of individual EEC peptides on intestinal function by generating EEC-deficient human intestinal organoids from pluripotent stem cells. We recently used this model system to show that some EECs regulate ion-coupled nutrient absorption in neighboring cells. Because EECs are nutrient-sensing cells, we considered that they might coordinate other intestinal responses to nutrient availability. Most EEC peptides signal via G-protein coupled receptors which activate second messengers to modulate the function of their target cell. These second messengers are intimately linked to ancient regulators of cellular metabolism, such as mammalian target of rapamycin (mTOR), which are known to play essential roles in many intestinal functions. This proposal will test the hypothesis that EECs regulate cellular metabolism in the stem cell niche (Aim 1) and in the differentiated enterocyte (Aim 2), thus impacting both intestinal homeostasis and efficiency of nutrient absorption. As EECs are now common targets for the treatment of type 2 diabetes, understanding how EECs affect intestinal metabolism and function will inform how dietary or pharmacological manipulation of EECs will impact gut health, nutrient absorption, and whole-body metabolism. To ensure success of the proposed research strategy, Dr. McCauley requires additional mentored time to become fluent in metabolic and metabolomic assays. Dr. McCauley has obtained a co-mentor, Dr. Kenneth Setchell, an international expert in using Mass Spectrometry to understand nutrition- and digestive disease- related changes in metabolism. Dr. McCauley proposes a rigorous yet feasible schedule of formal and informal training opportunities in metabolomics. At the conclusion of the mentored portion of her training, Dr. McCauley will be established as a fully independent, leading young investigator in the field of gastrointestinal metabolism, a critically understudied niche in the GI community.

项目概要 Heather McCauley 博士由辛辛那提儿童医院医疗中心的 James Wells 博士指导 中心（CCHMC），全国最大的儿科研究机构。 CCHMC 在 NIH 支持中排名第二 2017 年成立，是 NIDDK 赞助的消化疾病研究中心的所在地，该中心拥有充满活力的社区 医生和科学家。 CCHMC 为年轻研究者提供了非常支持的培训环境。博士。 麦考利提出了一项创新的跨学科研究计划，该计划将发育生物学、干细胞 细胞和类器官医学、胃肠病学和营养学、内分泌学和新陈代谢。 肠内分泌细胞 (EEC) 是专门的肠上皮细胞，可分泌 20 多种 生物活性肽可调节饱腹感、肠道蠕动、葡萄糖稳态、营养吸收和全身 新陈代谢对摄入的营养物质作出反应。虽然 EEC 激素的全身靶标是众所周知的， 比如大脑和胰腺，EEC肽对肠道本身功能的调节作用是 令人惊讶的是，研究不足。我们的实验室开发了一种独特的高通量人体模型系统来测试 单个 EEC 肽通过生成 EEC 缺陷的人类肠道类器官对肠道功能的作用 来自多能干细胞。我们最近使用这个模型系统来表明一些 EEC 调节离子耦合 邻近细胞的营养吸收。由于 EEC 是营养敏感细胞，我们认为它们 可能协调其他肠道对营养可用性的反应。大多数 EEC 肽通过 G 蛋白发出信号 偶联受体激活第二信使以调节靶细胞的功能。这些 第二信使与古代细胞代谢调节因子密切相关，例如哺乳动物 雷帕霉素（mTOR）的靶标，已知其在许多肠道功能中发挥重要作用。这 该提案将检验以下假设：EEC 调节干细胞生态位中的细胞代谢（目标 1）和 分化的肠上皮细胞（目标 2），从而影响肠道稳态和营养效率 吸收。由于 EEC 现在是治疗 2 型糖尿病的常见靶点，因此了解 EEC 如何发挥作用 影响肠道代谢和功能将告知 EEC 的饮食或药物操作将如何 影响肠道健康、营养吸收和全身代谢。 为了确保拟议研究策略的成功，麦考利博士需要额外的指导时间 熟练掌握代谢和代谢组学检测。麦考利博士获得了一位共同导师肯尼思博士 Setchell，一位使用质谱来了解营养和消化疾病的国际专家 相关的新陈代谢变化。麦考利博士提出了一个严格但可行的正式和非正式时间表 代谢组学方面的培训机会。在培训的指导部分结束时，麦考利博士 将成为胃肠代谢领域完全独立、领先的年轻研究者， 地理标志界中一个尚未得到充分研究的利基市场。