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.

项目摘要 希瑟·麦卡利（Heather McCauley）博士在辛辛那提儿童医院的詹姆斯·威尔斯（James Wells）博士指导 中心（CCHMC）是美国最大的儿科研究机构。 CCHMC在NIH支持中排名第二 2017年，是NIDDK赞助的消化疾病研究中心的所在地 医师和科学家。 CCHMC为年轻调查人员提供了非常支持性的培训环境。博士 McCauley提出了一个创新的跨学科研究计划，该计划桥接了发育生物学，STEM 细胞和器官医学，胃肠病学和营养，内分泌学和代谢。 肠内分泌细胞（EEC）是专门的肠上皮细胞，分泌超过20 生物活性刺激性调节饱腹感，肠道运动，葡萄糖稳态，营养滥用和全身 代谢响应摄入的养分。虽然EEC激素的全身靶标是众所周知的 例如大脑和胰腺，EEC肽在确定肠本身功能中的作用是 令人惊讶地理解。我们的实验室开发了一个独特的高通量人类模型系统，以测试 通过产生EEC缺陷的人肠癌，单个EEC肽在肠功能上的作用 来自多能干细胞。我们最近使用此模型系统表明某些EEC调节离子耦合 邻近细胞中的营养痛苦。因为EEC是营养感应细胞，我们认为它们 也许协调对养分利用率的其他肠反应。大多数EEC肽通过G蛋白信号 耦合的受体激活第二使者以调节其目标细胞的功能。这些 第二使者与蜂窝代谢的古代调节剂（例如哺乳动物）密切相关 雷帕霉素（MTOR）的靶标，已知在许多肠功能中起着重要作用。这 提案将检验以下假设，即EEC调节干细胞生态位的细胞代谢（AIM 1）和 分化的肠上皮细胞（AIM 2），从而影响肠内稳态和营养效率 抽象。由于EEC现在是治疗2型糖尿病的常见目标，因此了解EEC如何 影响肠道新陈代谢和功能将告知EEC的饮食或药物操纵 影响肠道健康，营养滥用和全身代谢。 为了确保拟议的研究策略的成功，McCauley博士需要额外的时间 流利的代谢和代谢组分测定。 McCauley博士获得了肯尼斯博士的院长 Setchell是使用质谱法来了解营养和消化疾病的国际专家 新陈代谢的相关变化。 McCauley博士提出，正式和非正式的严格但可行的时间表 代谢组学的培训机会。在培训的修改部分结束时，麦考利博士 将建立为胃肠道代谢领域的完全独立的，领先的年轻研究者， 在胃肠道社区中，人们对利基市场有着敏锐的了解。