The role of enteroendocrine cell differentiation in the success of bariatric surgery

项目摘要： 研究减肥手术成功背后的机制的最突出的原因之一是 用非侵入性治疗复制手术结果(S)。垂直袖状胃切除术(VSG)是目前世界上最大的胃切除手术之一 世界上经常进行的减肥手术，导致显著的体重减轻和显著的缓解 1年内发生T2 DM。餐后肠道分泌肽水平的急剧增加，如 胰高血糖素样肽-1(GLP-1)、胃抑制多肽(GIP)、多肽YY(PYY)和缩胆囊素 (CCK)，在VSG因其作用而被假设为手术成功的关键机制之后 在饱腹感和葡萄糖动态平衡方面。肠肽是在肠上皮细胞中制造的，我们(和其他人) 观察VSG增加分泌GLP-1的肠内分泌细胞(EEC)的数量。我们希望解决的一个关键问题 要解决的是，是什么推动了VSG之后的EEC分化，这种EEC分化是否仅限于GLP- 1-分泌细胞或其他EEC，以及这种增加是否有助于减肥和改善 血管紧张素转换酶可见血糖稳态。我们的初步数据表明，VSG明显改变了肠道 包括EEC在内的几种调节肠道分泌细胞发育的基因的表达 差异化。使用一种新的肠道器官模型(肠样体)，我们接下来演示了特定的 胆汁酸亚型增加分泌GLP-1的EECs。因此，我们假设胆汁中增加的 VSG后的酸分泌影响ISC向EECS的命运，这对减肥手术的结果至关重要。 在这里，我们提出了一种结合使用人和小鼠的体外和体内互补研究。 肠样体和小鼠的遗传操作与VSG手术的测试有以下具体目的：1)测试 胆汁酸驱动EEC分化的假说；2)ISC命运调节影响身体的假说 体重和血糖动态平衡；3)检验假设：增加EEC分化对VSG是必要的 结果。这一研究计划有望对理解ISC做出重大贡献 动态平衡和确定手术引起的肠肽水平升高的来源 最终目标是开发减肥手术的替代策略。在赠款期间，桑多瓦尔博士， 世卫组织是内分泌学和减肥外科方面的专家，将提供一个特殊的研究环境和 科罗拉多大学安舒茨医学院的资源，并提供研究指导 战略、助学金撰写、实验室管理以及网络和交流。英格博士，邓普西(CU)， 萨缪尔森、斯宾塞(UM)和塞苏帕西(康奈尔大学)是减肥手术方面的专家， 发展和/或干细胞生物学，将提供额外的指导和培训活动，详见 职业发展活动。成功实现目标将把我带到NIH资助的独立机构 研究人员研究VSG以非侵入性策略重现其手术益处的机制 医学部对肥胖和2型糖尿病的治疗。

Project Abstract: One of the most prominent reasons to study the mechanisms underlying the success of bariatric surgery is to replicate surgery outcomes with non-invasive treatment(s). Vertical sleeve gastrectomy (VSG), one of the most frequently performed bariatric surgeries in the world, results in substantial weight loss and dramatic remission of T2DM within 1 year. The drastic postprandial increase in the levels of gut-secreted peptides, such as glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), and cholecystokinin (CCK), after VSG has been hypothesized to be a critical mechanism of surgical success because of their roles in satiety and glucose homeostasis. The gut-peptides are made in the intestinal epithelium, and we (and others) see that VSG increases the number of GLP-1-secreting enteroendocrine cells (EEC). A key question we wish to address is what drives the EEC differentiation after VSG, whether this EEC differentiation limited to the GLP- 1-secreting cells or the other EECs, and whether this increase contributes to weight loss and improvements in glucose homeostasis seen with VSG. Our preliminary data demonstrate that VSG alters explicitly intestinal stem cell (ISC) expression of several genes that regulate intestinal secretory cell development including EEC differentiation. Using a novel intestinal organoid model (enteroids), we next demonstrated that specific subspecies of bile acids increase the GLP-1-secreting EECs. Hence, we hypothesize that the increased in bile acid secretion after VSG impacts the ISC fate towards EECs and this is critical to bariatric surgery outcomes. Here, we propose a combination of complementary in vitro and in vivo studies using human and mouse enteroids and mouse genetic manipulation with VSG surgery to test the following specific aims: 1) test hypothesis that bile acids drive EEC differentiation; 2) test hypothesis that modulation of ISC fate affects body weight and glucose homeostasis; 3) test hypothesis that increased EEC differentiation is necessary for VSG outcomes. This research plan is expected to make a significant contribution to the understanding of ISC homeostasis and to determine the origin of the surgery-induced increase in gut-peptides levels with the ultimate goal of developing an alternative strategy to bariatric surgery. During the grant period, Dr. Sandoval, who is an expert in endocrinology and bariatric surgery, will provide an exceptional research environment and resources at the University of Colorado Anschutz Medical Campus and also provide guidance in research strategy, grant writing, lab management, and networking and communication. Drs. Inge, Dempsey (CU), Samuelson, Spence (UM) and Sethupathy (Cornell University), who are experts in bariatric surgery, developmental and/or stem cell biology, will provide additional guidance and training activities as detailed in the Career development activity. Successfully achieved aims will lead me to a NIH-funded independent researcher studying the mechanism of VSG to reproduce its surgical benefits with a non-invasive strategy in the treatment the obesity and T2DM within a medical sciences department.