Gastric X/A Like Cells in Health and Diseases

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。

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.