Project Number: 6250-51000-051-03
Project Type: Specific Cooperative Agreement

Start Date: Oct 01, 2005
End Date: Sep 30, 2010

Objective:
The objective of this cooperative research is to establish the physiological role of lactoferrin in neonatal development; determine the importance of insulin receptor substrates (IRS) -1 and -2 to lactogenesis in the mouse; discover the mechanism of intracellular glucose transporter targeting in lactating mammary gland; determine how obesity and undernutrition alter pregnancy-induced metabolic/physiologic adaptations leading to adverse complications to mother and fetus; determine the regulation of the casein gene cluster domain in the synthesis of milk proteins during lactation; determine if there is a finite period during which the human neonate maximally utilizes protein intake for growth, to define this period, to determine if a higher protein intake during this period improves early growth without unacceptable metabolic consequences and to determine if improved growth during this period reduces subsequent growth and neurodevelopmental deficits. 1) Physiological Role of Lactoferrin in Neonatal Development and Host Defense - Develop a greater understanding for the enhanced development and host protection that is observed in the breast-fed versus formulae-fed infants. 2) Insulin and IGF Signaling in Lactogenesis - Gain an understanding of the mechanisms of insulin/IGF-I actions in the lactating mammary gland. 3) Utilization of Dietary Protein During Early Infancy - 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) Relationship between Maternal Nutritional Status and Pregnancy Outcome - Aims to 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) Nutritional Pathogenesis, Treatment and Prevention of Childhood Malnutrition - 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) Functional Genomics of the Casein Gene Cluster Region - 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) Nutritional and Functional Sulfur Amino Acid Requirements in Healthy Children - Understand amino acid metabolism and requirements for nutritional and functional balance under conditions of health and disease in children.

Approach:
1) Physiological Role of Lactoferrin in Neonatal Development and Host Defense - 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) Insulin and IGF Signaling in Lactogenesis - 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) Utilization of Dietary Protein During Early Infancy - 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) Relationship between Maternal Nutritional Status and Pregnancy Outcome - 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) Nutritional Pathogenesis, Treatment and Prevention of Childhood Malnutrition - 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) Functional Genomics of the Casein Gene Cluster Region - Analyze the chromatin structure and by analysis of transgenic mice harboring large BAC based transgenes with deletions or mutations of evolutionary conserved regions. 7) Nutritional and Functional Sulfur Amino Acid Requirements in Healthy Children - 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.