Project Number: 6250-51000-045-00
Project Type: Appropriated

Start Date: May 21, 2004
End Date: Apr 30, 2009

Objective:
The overriding goal of this research is to provide unique information regarding the regulation of mineral requirements by genetic, hormonal and developmental factors. This will allow for rational approaches to dietary interventions in children and understanding of the causes of mineral deficiency conditions. Specific objectives are 1) determine the mineral requirements of small children and the effects of specific dietary intake and nutrient interactions on these requirements; 2) determine the genetic regulators of zinc status using an animal model and then applying genetic methods to evaluate the effects of these regulatory genes in humans with zinc deficiency; and 3) to understand the role of leptin in relation to bone formation as well as other hormonal and genetic factors involved in the control of bone mass.

Approach:
These studies will utilize state-of-art isotopic and genetic methodology to evaluate nutrient requirements and genetic factors regulating zinc metabolism and bone mass. Studies of nutrient requirements of children will be done by enrolling toddlers and small children one through three years of age (12 to 48 months). Calcium, iron, zinc, magnesium, and copper absorption will be measured at the 25th to 75th percentile of usual American intakes. Subsequently, we will assess the effects of dietary inhibitors (phytates) and enhancers (ascorbic acid) of nutrient absorption on the absorption of key minerals. Additionally, we will look at the effects of changes in a key mineral ratio (Fe:Zn) on mineral absorption. Novel biomarkers of zinc status will be identified using a piglet model of zinc deficiency. RNA will be extracted from buccal cells and zinc deficient piglets, and from zinc sufficient piglets (and their organs). RNA will be screened for genes whose expression is significantly altered by zinc status using porcine DNA microarrays and real time PCR. The utility of these markers in humans will be assessed in three phases (1) an assessment of the variability of expression of these biomarkers in healthy, zinc sufficient humans, (2) the effect of experimental zinc depletion/repletion on expression, and (3) the effect of zinc supplementation on a disease model of zinc deficiency (cystic fibrosis). Studies of bone mass control will be conducted by evaluating the expression of the beta-2-adrenergic receptor in osteoblasts and the effects of this receptor of osteoblastic proliferation, differentiation and activity. The effects of peripheral and central leptin will be evaluated based on their effects on antiosteogenetic neurons in the hypothalamus. Specific neuropeptides, CART (cocaine and amphetamine regulated transcript) and NPY (Neuropeptide Y) will be investigated to determine if they are genetically downstream of leptin for its antiosteogenic and anorexigenic function.