Incretins and Nutrient induced Plasticity

肠促胰岛素和营养诱导的可塑性

基本信息

  • 批准号:
    RGPIN-2017-05996
  • 负责人:
  • 金额:
    $ 1.68万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2018
  • 资助国家:
    加拿大
  • 起止时间:
    2018-01-01 至 2019-12-31
  • 项目状态:
    已结题

项目摘要

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
肠促胰岛素和营养诱导的可塑性******肠道不是一个被动的管道,而是一个巨大的动态器官,它可以适应营养供应和能量需求的巨大变化。粘膜结构经历了强大的适应性,因为包括上皮细胞增殖、凋亡和分化在内的细胞过程可能在营养剥夺时下调,并在营养摄入后恢复。肠道是一个能量需求旺盛的器官,保持足够的工作能力来吸收营养,同时抵消代谢成本是至关重要的。肠内分泌L细胞和K细胞分别在餐后快速分泌胰高血糖素样肽1 (glucagon like peptide 1, GLP-1)和葡萄糖依赖性胰岛素营养多肽(glucose-dependent insulinotrophic polypeptide, GIP)。GLP-1和GIP分别通过不同的g蛋白偶联受体(GLP-1R和GIPR)发出信号,传统上认为GLP-1和GIP以胰岛为靶点,增加葡萄糖刺激的胰岛素分泌。然而,肠促胰岛素受体在整个胃肠道中表达,分泌GLP-1和GIP的肠内分泌细胞与肠腔、微血管和神经系统中的营养物质直接接触,使它们处于介导从禁食到进食状态的高度适应性反应的理想位置。本研究旨在识别和定义肠促胰岛素激素GIP和GLP-1在摄取营养物质时动态调节肠道结构和功能的新信号通路。******假设:肠道来源的肠促胰岛素激素、GLP-1和GIP介导肠道营养诱导的可塑性。***目的:为了明确肠促胰岛素激素介导营养诱导可塑性的作用机制,需要进行大量的关键实验。在野生型(WT)和双肠促胰岛素受体敲除小鼠(DIRKO)的对照组中,暴露于禁食或餐后条件下,我们将确定:(a)肠道的形态组成随着喂养而发生适当的变化,(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)肠道上皮细胞的凋亡和增殖,(e) 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。******申请人具有本提案中包含的所有技术的重要专业知识;因此,学员将获得一些互补和复杂的工具/方法来分离细胞和适当使用动物,以应用于他们未来的研究项目。******预期结果和相关性:我们期望确定GIPR和GLP-1R信号在介导小肠对营养摄入的适应中的关键作用。************ R

项目成果

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Mulvihill, Erin其他文献

Mulvihill, Erin的其他文献

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{{ truncateString('Mulvihill, Erin', 18)}}的其他基金

Incretins and Nutrient induced Plasticity
肠促胰岛素和营养诱导的可塑性
  • 批准号:
    RGPIN-2017-05996
  • 财政年份:
    2022
  • 资助金额:
    $ 1.68万
  • 项目类别:
    Discovery Grants Program - Individual
Incretins and Nutrient induced Plasticity
肠促胰素和营养诱导的可塑性
  • 批准号:
    RGPIN-2017-05996
  • 财政年份:
    2021
  • 资助金额:
    $ 1.68万
  • 项目类别:
    Discovery Grants Program - Individual
Incretins and Nutrient induced Plasticity
肠促胰素和营养诱导的可塑性
  • 批准号:
    RGPIN-2017-05996
  • 财政年份:
    2020
  • 资助金额:
    $ 1.68万
  • 项目类别:
    Discovery Grants Program - Individual
Incretins and Nutrient induced Plasticity
肠促胰素和营养诱导的可塑性
  • 批准号:
    RGPIN-2017-05996
  • 财政年份:
    2019
  • 资助金额:
    $ 1.68万
  • 项目类别:
    Discovery Grants Program - Individual
Incretins and Nutrient induced Plasticity
肠促胰岛素和营养诱导的可塑性
  • 批准号:
    RGPIN-2017-05996
  • 财政年份:
    2017
  • 资助金额:
    $ 1.68万
  • 项目类别:
    Discovery Grants Program - Individual

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肠促胰岛素和营养诱导的可塑性
  • 批准号:
    RGPIN-2017-05996
  • 财政年份:
    2022
  • 资助金额:
    $ 1.68万
  • 项目类别:
    Discovery Grants Program - Individual
Unconventional regulation of mTORC1 signaling by inositol phosphate: implications for nutrient-induced premature aging
磷酸肌醇对 mTORC1 信号传导的非常规调节:对营养诱导的过早衰老的影响
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