Cellular Molecular Mechanisms of Alanyl-Glutamine Oral Rehydration and Nutrition

项目摘要 巴西东北部的实验室和临床研究证明了一种新型丙氨酰的益处， 谷氨酰胺为基础的口服补液和营养治疗（Ala-Gln ORNT）在加速修复 在细胞培养、动物模型、艾滋病患者和 来自城市棚户区的儿童，肠道感染和营养不良的发病率很高。 Ala-Gln增强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， 肠道内环境稳定和修复机制的关键调节器。在以下方面的知识差距： 1)口服Ala-Gln改善营养不良儿童肠道完整性的最小有效剂量 和2）Ala-Gln改善肠道炎症的程度，进一步限制了我们的研究。 了解Ala-Gln ORNT作为腹泻恶性循环的有希望的干预措施， 在资源有限的环境中解决营养不良问题。在本建议中，我们将寻求进一步界定 使用最先进的分子和遗传学技术研究Ala-Gln的肠道修复机制 方法在断奶小鼠模型的营养不良和剂量反应研究， 营养不良的巴西儿童。我们的具体目标是：1）定义EGFR在以下方面的作用： 介导Ala-Gln ORNT逆转断奶小鼠营养不良诱导的肠病 2）确定Ala-Gln对营养不良模型的作用机制和量效关系。 恢复营养不良的巴西儿童的肠屏障功能。我们假设 1）EGFR是营养不良断奶仔猪对Ala-Gn的稳态应答所必需的 小鼠，2）口服Ala-Gln将改善营养不良儿童的肠道通透性， 剂量比以前测试，和3）口服Ala-Gln减少肠道炎症， 营养不良的儿童。拟议的研究将产生重要影响，不仅对 腹泻和营养不良，但其他几种传染病和消化系统疾病。此外，委员会认为， 这个出色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取得了成功。

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.