Research - Molecular, Cellular, And Regulatory Aspects Of Nutritional Metabolism During Childhood Development
Organ-Specific Metabolism and Growth under Varying Nutritional Conditions during Development
The first goal is to establish the critical window of development during which the growth potential of the skeletal musculature is compromised when the offspring are nurtured by protein-undernourished mothers and to elucidate the mechanisms responsible for the impaired muscle growth. The studies focus on the satellite cell (the differentiated muscle stem cell) because prior data suggest that it is the limiting factor for muscle growth. We will quantify in vivo differences in satellite cell turnover (proliferation, differentiation, and apoptosis) in muscles from the offspring of dams that are fed a moderately restricted protein diet during either gestation or lactation. In vitro approaches and in vivo cross-transplantation studies will be used to differentiate between the contributions of modifications intrinsic to the cell versus extrinsic factors in the regulation of satellite cell turnover. We anticipate that the results of these studies will contribute to our understanding of how the nutrition of the fetus and infant has lifelong consequences for the health of the individual.
The second goal is to obtain data that will enhance the development of nutritional guidelines for amino acid intakes during pregnancy, lactation, and in pathological conditions. The amino acids that are intermediate metabolites in the urea cycle are crucial in the detoxification of ammonia originated by amino acid oxidation and are key players in nitric oxide (NO) synthesis. Reduced availability or increased demand of the urea cycle intermediates occurs both in physiological (growth, pregnancy) and pathophysiological (trauma, sepsis) conditions, and their supplementation might be needed to meet their biological requirement. The metabolism of these amino acids will be fully explored using mouse models together with stable isotopic techniques. These data will have global applicability and provide a strong basis for the development of evidence-based nutritional recommendations.
Functional Genomics of Lactation: Effects of Genetics, Hormones and Substrates
The long-term goal of this project is the development of a genomic paradigm that will allow for a complete understanding of the genetic and environmental factors that regulate mammary gland function in lactating females. In the United States, exclusive breastfeeding is advocated for the first 6 months of life because of the established health benefits for both infant and mother. At present a significant number of women who choose to breastfeed are unable to do so successfully. An improved understanding of the genomic factors regulating mammary gland function is central to providing therapeutic interventions that can aid women to establish and maintain a productive lactation.
The studies outlined within this proposal will identify the genetic factors that regulate lactation and will broaden the current understanding of mechanisms that underlie the variability that exists in the lactation capacity of lactating females. In Objective 1 we will profile mammary gene expression in normal women and women known to struggle with the initiation and maintenance of lactation using gene array analyses of RNA derived from milk fat globules. Objective 2 will use mouse genomics to identify quantitative trait loci (QTL), which will determine mammary gland function and development in lactating females and then will determine how these loci affect lactation during maternal obesity. Objective 3 will determine the effect of nutritional interventions on the development, performance, gene expression profiles, and epigenetic status of the mammary gland. The novel genes identified in these objectives will serve as candidates for evaluation in future human clinical studies aimed at enhancing milk production in breastfeeding women.
Nutrient Regulation of Blood and Blood Vessel Formation
The circulatory system is the first organ system to form in the developing embryo, and is required to deliver nutrients and oxygen to, and remove waste products from, all tissues of the body. Thus, functional blood vessels and blood circulation are essential for growth and development. Abnormal formation of blood and blood vessels in adults is central to the progression of prevalent pathologies, including atherosclerosis, tumor angiogenesis, and anemia. Therefore, it is important to understand the cellular and molecular regulation of blood and blood vessel formation. These are the long-term goals of this research. This plan specifically focuses on the hypothesis that specific nutrients, such as retinoids, play an important role in the formation and maturation of blood vessels, as well as hematopoiesis, during embryonic development. Supportive evidence is provided by our preliminary data that demonstrate that a retinoic acid deficiency in utero (in Raldh2-/- mutants) yields lethal abnormalities in vascular structure and function, and decreased hematopoietic potential of mesodermal progenitors. We will further investigate, on a cellular and molecular level, the role of retinoid signaling in the regulation of these processes. These studies will employ transgenic mouse models to define the contribution of retinoids to blood and blood vessel formation in vivo, and well-controlled cell culture systems to aid in elucidating their cellular and molecular roles in these processes. Information gained from these studies will further the understanding of normal development and the role of nutrients, such as retinoids, therein.