BINDING OF HMG1 DOMAIN PROTEINS TO CISPLATINATED DOUBLE STRANDED DNA

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Human milk contains a complex and wide array of oligosaccharides, some of which protect against toxins and pathogens involved in diseases of infants and other diseases that strike the general population, such as AIDS. To document the effects from differences in infant diet, the oligosaccharides present in urine and feces from breast-fed and formula-fed infants are being compared. In an earlier phase of this program, we have isolated the single component of human milk responsible for the observed inhibition of the diarrhea associated with the stable toxin (ST) of Escherichia coli in the suckling mouse, an established model for ST activity in humans, andhave partially characterized this molecule as a small fucosylated oligosaccharide that we have designated QV. We are currently working to isolate and fully characterize the molecular structure of QV, determine the mechanism whereby it protects against ST.- and develop an analytical method for measuring QV levels in milk. We will test the relationship between QV levels in milk andST-related disease in the nursling, synthesize QV, or find suitable alternate natural sources; andtest the efficacy of QV in preventing ST-related disease in humans. Thus, the overall direction of this project is to move from a clinical observation (lower incidence of gastroenteritis in breastfed infants) to the isolation and characterization of a specific non-immunoglobulin human milk factor that inhibits ST-induced secretory diarrhea in the infant mouse model, to understanding its mechanism of action, producing large amounts of the active factor, and testing itsefficacy in preventing gastroenteritis irr a human population. This work not only directly addresses the problem of ST-related diarrhea, but is a model for a potential role for other putativepathogen receptor analogs from human milk that protect nursing infants from enteric pathogens.