Project Number: 6250-51000-048-00
Project Type: Appropriated

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

Objective:
1) Develop a greater understanding for the enhanced development and host protection that is observed in the breast-fed versus formulae-fed infants. 2) Gain an understanding of the mechanisms of insulin/IGF-I actions in the lactating mammary gland. 3) Determine if there is a finite period during which the human neonate maximally utilizes protein intake for growth, to define this period and to determine if a higher protein intake during this period improves early growth without unacceptable metabolic consequences and reduces subsequent growth and neurodevelopmental deficits. 4) Provide a better understanding of how maternal obesity and undernutrition alter the metabolic/physiologic adaptations necessary for a successful pregnancy and thereby will test nutritional therapies aimed at reducing or correcting their adverse outcomes. 5) Poor complementary feeding practices and zinc deficiency are two of the most important nutritional problems for young children worldwide. The consequences are retarded physical and intellectual development, as well in increased child morbidity and mortality. The objective is to develop and test novel strategies that have the potential to solve these problems in a population of high-risk children. 6) Understand the regulation of the casein genes and the genomic domain in which these genes reside, since Caseins (CSN) constitute the major nutritional proteins in milk and supply basic amino acids, calcium, phosphates and bioactive peptides (e.g. anti-microbial and opioid). 7) Understand amino acid metabolism and requirements for nutritional and functional balance under conditions of health and disease in children.

Approach:
1) Use generated LF knockout mice (LFKO) and two novel genetic mouse models that direct overexpression of LF to the small or large intestine, respectively, using intestinal-specific promoters. These unique gain-of-function transgenic mice will be used to investigate the effects of LF on iron homeostasis and host protection in the intestine of post weaning and adult mice thus eliminating any confounding factors in milk that may mask the functional properties(s) of LF during the suckling period. 2) Use mice that carry targeted inactivating germline mutations in the genes for IRS-1 or IRS-2 in combination with mammary tissue transplantation and primary cell culture approaches to determine the importance of activation of these signaling proteins in mammary cells to milk synthesis and/or mammary cell survival. 3) By testing if there is a finite period during early life when the infant maximally utilizes protein for growth and that failure to provide sufficient protein during this period results not only in short-and long-term growth deficits but also suboptimal neurodevelopment and by defining the period of maximum protein utilization for growth and the impact of size for gestational age as well as formula-feeding vs. breast-feeding on this period will be defined. 4) Perform a series of experiments of obese pregnant women and underweight teenagers in Houston and in underweight and normal weight adult women in India to test a series of hypotheses. 5) Develop a micronutrient-rich, energy-dense ready-to-use food and compare it to a fish-fortified porridge as a complementary food in 6-18 month old children. The quantity and quality of consumed breast milk will be measured and children will be followed longitudinally. The role of asymptomatic intestinal malabsorption in zinc homeostasis will be investigated in 3-5 year old children, using site specific gastrointestinal sugar absorption tests and zinc stable isotope techniques. 6) Analyze the chromatin structure and by analysis of transgenic mice harboring large BAC based transgenes with deletions or mutations of evolutionary conserved regions. 7) Methionine requirements that maintain nutritional balance and glutathione synthesis rates in health adolescent children will be studied through using intravenous indicator amino acid oxidation and balance technique.