Cellular Molecular Mechanisms of Alanyl-Glutamine Oral Rehydration and Nutrition

项目总结 巴西东北部的实验室和临床研究证明了一种新的丙氨基- 以谷氨酰胺为基础的口服补液和营养疗法(ALA-GLN或NT)加速修复 细胞培养、动物模型、艾滋病患者和 来自肠道感染和营养不良高发城市棚户区的儿童。 丙氨酸-谷氨酰胺促进肠屏障修复的机制尚不清楚；然而， 来自我们实验室的最新数据表明，表皮生长因子受体(EGFR)的作用， 肠道内环境平衡和修复机制的关键调节器。在以下方面的知识差距： 1)口服丙氨酸-谷氨酰胺改善营养不良儿童肠道完整性的最小有效剂量 和2)丙氨酸-谷氨酰胺改善肠道炎症的程度，进一步限制了我们的 了解ALA-Gln或NT作为一种有希望的干预腹泻和腹泻的恶性循环 在资源有限的情况下营养不良。在这项建议中，我们会寻求进一步界定 丙氨酸-谷氨酰胺肠道修复机制的分子遗传学研究进展 一种营养不良的断奶小鼠模型的方法和一项剂量-反应研究 营养不良的巴西儿童。我们的具体目标是：1)确定EGFR在 ALA-Gln逆转断奶小鼠营养不良所致肠病的实验研究 2)测定丙氨酸-谷氨酰胺的作用机制和量效关系。 营养不良的巴西儿童肠屏障功能的恢复。我们假设 结论：1)营养不良断奶仔猪对ALA-Gn的动态平衡反应需要EGFR 小鼠，2)口服丙氨酸-谷氨酰胺能改善低营养不良儿童的肠道通透性 3)口服丙氨酸-谷氨酰胺可减少小鼠的肠道炎症 营养不良的儿童。拟议的研究不仅对以下方面具有重要影响 腹泻和营养不良，但其他几种感染性和消化系统疾病。此外， 这一绝佳的培训机会将为我提供必要的基础 作为一名独立的全球健康科学家，他取得了成功的职业生涯。

PROJECT SUMMARY Laboratory and clinical studies in Northeast Brazil demonstrate the benefits of a novel alanyl- glutamine-based oral rehydration and nutrition therapy (Ala-Gln ORNT) in speeding the repair of damaged intestinal barrier function in cell culture, animal models, patients with AIDS, and in children from an urban shantytown with a high incidence of enteric infections and undernutrition. The mechanisms by which Ala-Gln enhances intestinal barrier repair remain unclear; however, recent data from our laboratory suggest a role of the epidermal growth factor receptor (EGFR), a key regulator of intestinal homeostasis and repair mechanisms. Gaps in knowledge regarding: 1) the minimal effective dose of oral Ala-Gln to improve gut integrity in undernourished children and 2) the extent to which Ala-Gln ameliorates intestinal inflammation, further limit our understanding of Ala-Gln ORNT as a promising intervention for the vicious cycle of diarrhea and undernutrition in resource-limited settings. In this proposal, we will seek to further define the mechanisms of intestinal repair by Ala-Gln using state-of-the art molecular and genetic approaches in a weanling mouse model of malnutrition and a dose-response study in undernourished Brazilian children. Our Specific Aims are to: 1) Define the role of EGFR in mediating the Ala-Gln ORNT reversal of malnutrition-induced enteropathy in a weanling mouse model of malnutrition, and 2) determine the mechanisms and dose-effects of Ala-Gln for restoration of intestinal barrier function in undernourished Brazilian children. We hypothesize that: 1) EGFR is required for homeostatic responses to Ala-Gn in undernourished weanling mice, 2) oral Ala-Gln will improve intestinal permeability in undernourished children at lower doses than previously tested, and 3) oral Ala-Gln reduces intestinal inflammation in undernourished children. The proposed studies will have important implications not only for diarrhea and malnutrition, but for several other infectious and digestive disorders. Furthermore, this outstanding training opportunity will provide me with the foundation necessary for a successful career as an independent global health scientist.