Enteroendocrine Regulation of Intestinal Metabolism

肠道代谢的肠内分泌调节

• 批准号: 10816027
• 负责人: Heather A McCauley
• 金额: $ 15.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 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/10816027
• 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 Cells; Epithelium; 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; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Organ; Organoids; Pancreas; Paneth Cells; Parenteral Nutrition; Pathway interactions; Patients; Pediatric Hospitals; Pediatric Research; Peptide Signal Sequences; Peptides; Physiology; Play; Pluripotent Stem Cells; Production; Proliferating; 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; Vomiting; Work; 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; large scale production; metabolic rate; metabolomics; mouse model; novel; novel therapeutics; nutrient absorption; nutrition; paracrine; pharmacologic; response; single cell analysis; single-cell RNA sequencing; stem cell function; 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.

项目总结