The proposed 5-year Program-Project grant addresses unresolved questions about the developmental effects of iron deficiency of brain and behavior. Based on exciting new basic research, the program targets CNS processes on myelination, neurotransmission, neuronal metabolism, particular brain regions (hippocampus and basal ganglia, especially striatum) and associated behaviors. The program considers the effects of the timing of iron deficiency and its treatment, depending on developmental stage. This integrated cross-species program consists of 1 human infant study; 2 no-human primate projects, and 1 rodent study, with 3 cores (administrative, analytic, and statistical ). The component projects, with inter-disciplinary collaboration among leading clinical and basic science researchers, are tightly linked conceptually and methologically, designed so that each project has a special but complementary role. Project I (human infant) emphasizes promising new non-invasive ways to assess CNS functions in babies. Project II (monkey infant-Davis) and Project III (monkey infant-Madison) use hamtologic and behavioral measures parallel to Project I and to each other to establish two different primate models. Project II involves diet-induced discrete time periods of iron deficiency during much of gestation and lactation. The timing and conditions of iron deficiency and its treatment are thus systematically varied in the two models. CSF analyses, drug challenge studies, and neuroimaging assess the brain more directly. Project IV (developing rodent) uses comparable developmental windows and behavioral functions and includes tissue and imaging analyses to clarify underlying mechanisms. Individually, each project represents a substantial leap beyond any previous research on early iron deficiency. Collectively, the program will make a major contribution in understanding developmental effects of iron deficiency, the world's most common single nutrient disorder.
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