Enteroendocrine Regulation of Intestinal Metabolism

项目总结 希瑟·麦考利医生由辛辛那提儿童医院医疗中心的詹姆斯·威尔斯医生指导 中国儿科研究中心(CCHMC)是中国最大的儿科研究机构。年，CCHMC在NIH支持方面排名第二 2017年，是NIDDK赞助的消化系统疾病研究中心的所在地，拥有一个充满活力的社区 医生和科学家。CCHMC为年轻的调查人员提供了一个非常支持性的培训环境。Dr。 麦考利提出了一项创新的跨学科研究计划，该计划架起了发育生物学、STEM 细胞和有机医学、胃肠病学和营养学、内分泌学和新陈代谢。 肠内分泌细胞(EECS)是一种专门化的肠上皮细胞，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多肽 新陈代谢对摄取的营养作出反应。虽然EEC激素的系统靶点是众所周知的， 如大脑和胰腺，EEC多肽在调节肠道本身功能方面的作用是 令人惊讶的是，研究不足。我们的实验室开发了一种独特的、高通量的人体模型系统来测试 单个EEC多肽通过产生EEC缺陷的人肠道器官类物质对肠道功能的影响 来自多能干细胞。我们最近用这个模型系统证明了一些EEC调节离子偶联 邻近细胞的养分吸收。由于EECs是营养感应细胞，我们认为它们 可能会协调其他肠道对营养供应的反应。大多数EEC多肽通过G蛋白传递信号 偶联受体，激活第二信使以调节其靶细胞的功能。这些 第二信使与古老的细胞新陈代谢调节器密切相关，例如哺乳动物 雷帕霉素的靶标(MTOR)，已知在许多肠道功能中发挥重要作用。这 该提案将检验EECS在干细胞利基中调节细胞新陈代谢的假设(目标1)和 分化的肠细胞(目标2)，从而影响肠道内环境的稳定和营养的效率 吸收。由于EECS现在是治疗2型糖尿病的常见靶点，了解EECS是如何 影响肠道新陈代谢和功能将决定EECS的饮食或药物操作将如何 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策略的成功，麦考利博士需要更多的指导时间 熟练掌握新陈代谢和代谢组学分析。麦考利博士找到了一位共同导师，肯尼斯博士 塞切尔是一位利用质谱学了解营养和消化系统疾病的国际专家-- 新陈代谢的相关变化。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。在她的培训指导部分结束时，麦考利博士 将被确立为胃肠道代谢领域完全独立的、领先的年轻研究人员， 这是GI社区中一个被严重低估的利基市场。

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.