Cellular Molecular Mechanisms of Alanyl-Glutamine Oral Rehydration and Nutrition

描述（由申请方提供）：巴西东北部的实验室和临床研究证明了一种新型丙氨酰-谷氨酰胺口服补液和营养疗法（Ala-Gln ORNT）在加速细胞培养、动物模型、艾滋病患者以及肠道感染和营养不良发生率高的城市棚户区儿童中受损肠道屏障功能修复方面的获益。Ala-Gln增强肠屏障修复的机制尚不清楚;然而，我们实验室最近的数据表明表皮生长因子受体（EGFR）的作用，EGFR是肠内稳态和修复机制的关键调节因子。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，进一步限制了我们对Ala-Gln ORNT作为资源有限环境中腹泻和营养不良恶性循环的有希望干预的理解。在这项提案中，我们将寻求进一步确定肠修复的机制，由丙氨酸-谷氨酰胺使用国家的最先进的分子和遗传学方法在断奶小鼠模型的营养不良和营养不良的巴西儿童的剂量反应研究。我们的具体目标是：1）在营养不良的断奶小鼠模型中，确定EGFR在介导营养不良诱导的肠病的Ala-Gln ORNT逆转中的作用，和2）确定Ala-Gln在营养不良的巴西儿童中恢复肠屏障功能的机制和剂量效应。我们假设：1）EGFR是营养不良断奶小鼠对Ala-Gn的稳态反应所必需的，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，3）口服Ala-Gln减少营养不良儿童的肠道炎症。拟议中的研究不仅对腹泻和营养不良，而且对其他几种传染病和消化系统疾病都有重要意义。此外，这次出色的培训机会将为我作为一名独立的全球健康科学家的成功职业生涯奠定必要的基础。 公共卫生相关性：腹泻病和与疟疾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。我们的建议解决了一种新的丙氨酰-谷氨酰胺口服补液和营养治疗（Ala-Gln ORNT）的机制，作为一种有前途的干预急性和长期的营养作用的腹泻，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.