Enteroendocrine Regulation of Intestinal Metabolism

项目摘要 石楠麦考利博士是由詹姆斯威尔斯博士在辛辛那提儿童医院医疗指导 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，是NIDDK赞助的消化疾病研究中心的所在地， 医生和科学家。CCHMC为年轻的研究人员提供了一个非常支持性的培训环境。博士 麦考利提出了一个创新的跨学科的研究计划，桥梁发育生物学，干 细胞和类器官医学、胃肠病学和营养学、内分泌学和代谢学。 肠内分泌细胞（EECs）是一种特殊的肠上皮细胞，分泌20多种 调节饱腹感、肠道运动、葡萄糖稳态、营养吸收和全身的生物活性肽 代谢对摄入的营养素的反应。虽然EEC激素的全身靶点是众所周知的， 例如脑和胰腺，EEC肽在调节肠本身功能中的作用是 令人惊讶地被忽视了。我们的实验室开发了一种独特的高通量人体模型系统， 单个EEC肽通过产生EEC缺陷的人肠类器官对肠功能的作用 从多能干细胞。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。由于内皮细胞是营养敏感细胞，我们认为它们 可能会协调其他肠道对营养可用性的反应。大多数EEC肽通过G蛋白信号传导 偶联受体激活第二信使调节其靶细胞的功能。这些 第二信使与细胞代谢的古老调节因子密切相关，例如哺乳动物， 雷帕霉素靶点（mTOR），已知其在许多肠道功能中起重要作用。这 这项提案将检验这一假设，即内皮细胞调节干细胞龛（Aim 1）中的细胞代谢， 分化的肠上皮细胞（目标2），从而影响肠道内稳态和营养效率 吸收由于EECs现在是治疗2型糖尿病的常见靶点，了解EECs如何 影响肠道代谢和功能将告知如何饮食或药理学操作的内皮细胞将 影响肠道健康、营养吸收和全身新陈代谢。 为了确保拟议的研究战略的成功，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分析。麦考利博士有一位共同导师肯尼斯博士 Sethoff是一位国际专家，他使用质谱法来了解营养和消化系统疾病， 代谢的相关变化。麦考利博士提出了一个严格而可行的正式和非正式的时间表 代谢组学的培训机会。在她的培训指导部分结束时，麦考利博士 将成为胃肠道代谢领域完全独立的、领先的年轻研究者， 这是GI界一个被严重忽视的领域

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.