Cellular Molecular Mechanisms of Alanyl-Glutamine Oral Rehydration and Nutrition

描述(申请人提供)：巴西东北部的实验室和临床研究表明，在细胞培养、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中，一种基于丙氨酰-谷氨酰胺的新型口服补液和营养疗法(ALA-Gln Ornt)在加速修复受损的肠道屏障功能方面具有优势。Ala-Gln促进肠屏障修复的机制尚不清楚；然而，我们实验室的最新数据表明，表皮生长因子受体(EGFR)发挥了作用，EGFR是肠道内稳态和修复机制的关键调节因子。关于以下方面的认识存在差距：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；2)Ala-Gln改善肠道炎症的程度，进一步限制了我们对Ala-Gln作为一种有希望的干预措施的理解，即在资源有限的情况下，ALA-Gln可用于治疗腹泻和营养不良的恶性循环。在这项提案中，我们将利用最先进的分子和遗传学方法，在营养不良的断奶小鼠模型和巴西营养不良儿童的剂量-反应研究中，寻求进一步确定ALA-Gln对肠道修复的机制。我们的具体目标是：1)明确EGFR在ALA-Gln或逆转营养不良所致肠病中的作用；2)确定Ala-Gln恢复营养不良巴西儿童肠道屏障功能的机制和量效关系。我们假设：1)营养不良的断奶小鼠对Ala-Gn的动态平衡反应需要EGFR，2)口服Ala-Gln将以低于先前测试的剂量改善营养不良儿童的肠道通透性，以及3)口服Ala-Gln可减轻营养不良儿童的肠道炎症。拟议的研究不仅对腹泻和营养不良，而且对其他几种感染性和消化系统疾病都有重要影响。此外，这一绝佳的培训机会将为我作为一名独立的全球卫生科学家的成功职业生涯提供必要的基础。 公共卫生相关性：腹泻病和与腹泻相关的营养不良仍然是全世界发病率和死亡率的主要原因。我们的建议阐述了一种新的丙氨酰-谷氨酰胺口服补液和营养疗法(ALA-Gln Ornt)的机制，作为一种有希望的干预腹泻的急性和长期营养效应，从而有助于改善这种发病率和死亡率。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Diarrheal diseases and diarrhea-associated undernutrition remain predominant causes of morbidity and mortality worldwide. Our proposal addresses the mechanisms of a novel Alanyl-Glutamine oral rehydration and nutrition therapy (Ala-Gln ORNT) as a promising intervention for the acute and long-term nutritional effects of diarrhea and thus contribute to ameliorating this morbidity and mortality.