Cellular Molecular Mechanisms of Alanyl-Glutamine Oral Rehydration and Nutrition

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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.