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Gastric X/A Like Cells in Health and Diseases

健康和疾病中的胃 X/A 样细胞

基本信息

批准号：
10399643
负责人：
MICHAEL W. MULHOLLAND
金额：
$ 31.2万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-13 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10399643
关键词：
Affect American Amino Acids Appetite Stimulants Biological Body Weight Cell Nucleus Cells Data Desire for food Diabetes Mellitus Disease Eating Endocrine Energy Metabolism Equilibrium FRAP1 gene Fatty Liver Feeding behaviors Food Energy Food Intake Regulation Gastric Acid Gastric mucosa Goals HDAC5 gene Health High Fat Diet Hormones Hypothalamic structure Intake Metabolic Metabolic Control Metabolic Diseases Mus Neuraxis Nutrient Obesity Obesity Epidemic Pathway interactions Peptides Phosphorylation Play Production Regulation Resistance Role Signal Pathway Signal Transduction Site Societies Stomach Techniques Testing Transgenic Organisms Translations Vial device base design energy balance experimental study extracellular ghrelin insight metabolic rate novel therapeutic intervention obesity development peptide hormone treatment strategy

项目摘要

Project Abstract New insights from our studies and others indicate that the gastric mucosa may sense overall energy balance and control metabolic rate through fine-tuning the production of two counteracting hormones: ghrelin and nesfatin-1, in X/A like cells. Ghrelin, a 28-amino acid gastric peptide hormone, was originally identified as an orexigenic factor, and is the only known circulating hormone able to initiate food intake. X/A like cells has been discovered to also secrete the anorexigenic hormone nesfatin-1. Our data indicate that the balance of ghrelin and nesfatin-1 secretion regulates nutrient intake. Our studies also indicate that the mechanistic target of rapamycin (mTOR) signaling pathway in the gastric mucosa plays a critical role in the coordination of nutrient availability, ingestive behavior and metabolic activity. Based on these observations, we hypothesize that mTOR signaling regulates fuel sensing via gastric X/A like endocrine cells. This signaling pathway coordinates overall energy balance by differential regulation of the orexigenic hormone ghrelin and the anorexigenic hormone nesfatin-1. We propose 3 specific aims to investigate the function of the gastric mTOR pathway in the production of these peptides and thus their effects on appetite control and energy expenditure. Aim 1 is designed to test the hypothesis that organismal fuel status affects phosphorylation of mTOR in gastric X/A like cells, and that mTOR signaling differentially regulates ghrelin and nesfatin-1 production. Aim 2 will first examine the alternative AMPK-HDAC5-mTOR signaling pathway in the regulation of ghrelin and nesfatin-1. We will then test the hypothesis that S6K1 and 4EBP1 are mTOR downstream molecules regulating the reciprocal translation of ghrelin and nesfatin-1. Aim 3 will demonstrate that gastric mTOR signaling affects food intake, energy expenditure and body weight in mice vial acyl-ghrelin and nesfatin-1. Completion of this proposal will advance our understanding of the interaction between gastric X/A like cells and nutrient intake. These findings suggest a completely new therapeutic approach directed at gastric sites.

项目摘要我们的研究和其他研究的新见解表明，胃粘膜可能感觉到整体能量通过微调两种中和激素：Ghrelin的产生来平衡和控制代谢率和Nesfatin-1，在X/A样细胞中。Ghrelin是一种由28个氨基酸组成的胃肽激素，最初被鉴定为一种促食欲因子，是唯一已知的能够启动食物摄取的循环激素。X/A样细胞有已被发现还分泌厌食激素Nesfatin-1。我们的数据表明， Ghrelin和Nesfatin-1的分泌调节营养物质的摄入。我们的研究还表明，机械性目标雷帕霉素(MTOR)信号通路在胃粘膜中的协调作用起着关键作用营养可获得性、摄食行为和代谢活动。基于这些观察结果，我们假设 MTOR信号通过胃X/A样的内分泌细胞调节燃料感觉。这条信号通路通过对促食欲素和生长激素的不同调节来协调整体能量平衡厌食激素Nesfatin-1。我们提出了三个特定的目标来研究胃mTOR的功能在这些多肽的生产过程中，它们对食欲控制和能量消耗的影响。目的1是为了验证这样一个假设，即机体的燃料状态会影响胃中mTOR的磷酸化 X/A样细胞，mTOR信号对Ghrelin和Nesfatin-1的产生有不同的调节作用。目标2将首先研究替代AMPK-HDAC5-mTOR信号通路对Ghrelin和Nesfatin-1的调节。然后我们将检验S6K1和4EBP1是mTOR下游分子的假设 Ghrelin和Nesfatin-1的相互翻译。目标3将证明胃mTOR信号影响食物小鼠的摄入量、能量消耗和体重。完成这项工作这一建议将促进我们对胃X/A样细胞与营养摄入之间的相互作用的理解。这些发现表明了一种针对胃部的全新治疗方法。