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：
10183235
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 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10183235
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.

项目摘要我们和其他研究的新见解表明胃粘膜可能感知整体能量通过微调两种抵消激素的产生来平衡和控制代谢率：生长素释放肽和 nesfatin-1，存在于 X/A 样细胞中。 Ghrelin 是一种 28 个氨基酸的胃肽激素，最初被鉴定为一种促食欲因素，并且是唯一已知的能够启动食物摄入的循环激素。 X/A 样细胞有还发现它还能分泌抑制食欲的激素 nesfatin-1。我们的数据表明，余额 ghrelin 和 nesfatin-1 的分泌调节营养摄入。我们的研究还表明，机械目标胃粘膜中的雷帕霉素（mTOR）信号通路在协调营养可用性、摄入行为和代谢活动。根据这些观察，我们假设 mTOR 信号传导通过胃 X/A 样内分泌细胞调节燃料感应。该信号通路通过对促食欲激素胃饥饿素和胃饥饿素的差异调节来协调整体能量平衡厌食激素nesfatin-1。我们提出了 3 个具体目标来研究胃 mTOR 的功能这些肽的产生途径及其对食欲控制和能量消耗的影响。目标 1 旨在检验有机体燃料状态影响胃中 mTOR 磷酸化的假设 X/A 样细胞，并且 mTOR 信号传导差异调节 ghrelin 和 nesfatin-1 的产生。首先是目标2 检查 ghrelin 和 nesfatin-1 调节中的替代 AMPK-HDAC5-mTOR 信号通路。然后我们将检验 S6K1 和 4EBP1 是调节 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 信号传导影响食物小鼠小瓶酰基生长素释放肽和 nesfatin-1 的摄入量、能量消耗和体重。完成此该提案将增进我们对胃 X/A 样细胞与营养摄入之间相互作用的理解。这些发现提出了一种针对胃部部位的全新治疗方法。