Incretins and Nutrient induced Plasticity

肠促胰岛素和营养素诱导的可塑性 ** 肠道不是被动的管道，而是一个巨大的、动态的器官，可以根据营养供应和能量需求的巨大变化进行调整。粘膜的结构经历了强大的适应，因为细胞过程包括上皮细胞增殖、凋亡和分化可能随着营养剥夺而下调，并在营养摄入后恢复。由于肠道是一个需要能量的器官，因此保持足够的营养吸收工作能力，同时抵消代谢成本至关重要。胰高血糖素样肽1（GLP-1）和葡萄糖依赖性促胰岛素多肽（GIP）分别由肠内分泌L细胞和K细胞在餐后非常迅速地分泌。GLP-1和GIP各自通过不同的G蛋白偶联受体（分别为GLP-1R和GIPR）发出信号，传统上认为其靶向胰岛以增加葡萄糖刺激的胰岛素分泌。然而，肠降血糖素受体在整个胃肠道中表达，并且分泌GLP-1和GIP的肠内分泌细胞与肠腔、微血管系统和神经系统中的营养物质直接接触，使得它们理想地处于介导从禁食到进食状态的高度适应性反应的位置。 该提案旨在确定和定义新的信号通路，通过这些信号通路，肠促胰岛素激素GIP和GLP-1动态调节肠道的结构和功能，以响应摄入的营养素。假设：肠源性肠促胰岛素激素GLP-1和GIP介导肠营养诱导的可塑性。目的：为了确定肠促胰岛素激素介导营养诱导的可塑性的作用机制，需要进行一些关键实验。在暴露于空腹或餐后条件的野生型（WT）和双肠促胰岛素受体敲除小鼠（DIRKO）同窝对照中，我们将确定是否：（a）肠的形态组成随着进食而适当地改变，（B）上皮细胞的生长和分化，（c）肠促胰岛素信号传导对消化和营养吸收的影响，（d）肠上皮细胞的凋亡和增殖，（e）在GLP-1R和GIPR缺失的小鼠中，禁食或再喂养所需的关键效应物的表达水平和蛋白质水平是否被阻断。* * 申请人对本提案中包含的所有技术都具有重要的专业知识;因此，学员将获得一些用于分离细胞和适当使用动物的补充和复杂的工具/方法，以应用于他们未来的研究计划。* * 预期结果和相关性：我们预期确定GIPR和GLP-1 R信号在介导小肠适应营养摄入方面的关键作用。我的天啊

Incretins and Nutrient Induced Plasticity******The intestine is not a passive conduit but a large, dynamic organ which adjusts to large variations in both nutrient supply and energy demand. The structure of the mucosa undergoes robust adaptation as cellular processes including epithelial cell proliferation, apoptosis and differentiation may be downregulated with nutrient deprivation and recovered upon nutrient ingestion. As the gut is an energetically demanding organ, maintaining sufficient work capacity for nutrient absorption while offsetting metabolic cost is vital. Two incretin hormone peptides are secreted from enteroendocrine L cells and K cells respectively, glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP) very rapidly post-prandially. GLP-1 and GIP each signal through a distinct G-protein coupled receptor, the GLP-1R and GIPR respectively and are classically thought to target the islet to increase glucose-stimulated insulin secretion. However, the incretin receptors are expressed throughout the gastrointestinal tract and the enteroendocrine cells which secrete GLP-1 and GIP are in direct contact with nutrients in the intestinal lumen, the microvasculature and nervous system making them ideally situated to mediate the highly adaptive response from a fasted to fed state. This proposal aims to identify and define novel signaling pathways through which the incretin hormones GIP and GLP-1 dynamically regulate the structure and function of the intestinal tract in response to ingested nutrients.******Hypothesis: The gut derived incretin hormones, GLP-1 and GIP mediate intestinal nutrient-induced plasticity.***Objectives: In order to define the mechanisms underlying the role of the incretin hormones for mediating nutrient induced plasticity, a number of key experiments are required. In Wildtype (WT) and Double Incretin Receptor Knock Out mice (DIRKO) littermate controls exposed to fasting or post-prandial conditions we will determine if: (a) morphological composition of the gut changes appropriately with feeding, (b) cell growth and differentiation of the epithelium, (c) the effect of incretin signaling on digestion and nutrient absorption, (d) apoptosis and proliferation of the gut epithelium, (e) if the expression levels and protein levels of key effectors required for fasting or refeeding blocked in mice in which the GLP-1R and GIPR have been deleted. ******The applicant has significant expertise with all of the techniques included in this proposal; therefore trainees will acquire a number of complementary and sophisticated tools/approaches for isolating cells and appropriate use of animals to apply to their future research programs. ******Expected Results and Relevance: We anticipate identifying a critical role for GIPR and GLP-1R signaling in mediating the adaptation of the small intestine to nutrient intake. ************R