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 平衡和控制代谢率通过微调生产两个抵消激素：生长激素释放肽 和nesfatin-1。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，并且是唯一已知的能够启动食物摄入的循环激素。X/A样细胞具有 也被发现分泌促性腺激素nesfatin-1。我们的数据表明， 生长素释放肽和nesfatin-1分泌调节营养摄入。我们的研究还表明， 雷帕霉素（mTOR）信号通路在胃粘膜的协调中起着至关重要的作用， 营养素利用率、摄食行为和代谢活动。基于这些观察，我们假设 mTOR信号通过胃X/A样内分泌细胞调节燃料感受。这个信号通路 协调整体能量平衡的差异调节食欲激素胃饥饿素和 促性腺激素nesfatin-1。我们提出了3个具体的目标来研究胃mTOR的功能， 这些肽的产生途径，因此它们对食欲控制和能量消耗的影响。 目的1旨在验证机体燃料状态影响胃粘膜中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。Aim 2将首先 研究AMPK-HDAC 5-mTOR信号通路在ghrelin和nesfatin-1调节中的替代作用。 然后，我们将检验S6 K1和4 EBP 1是mTOR下游分子调节细胞凋亡的假设。 胃饥饿素和nesfatin-1的相互翻译。目的3将证明胃mTOR信号传导影响食物 摄入量、能量消耗和体重。完成本 该建议将促进我们对胃X/A样细胞与营养摄入之间相互作用的理解。 这些发现表明了一种针对胃部位的全新治疗方法。

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.