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United States Department of Agriculture

Agricultural Research Service

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Location: Children's Nutrition Research Center

2012 Annual Report

1a. Objectives (from AD-416):
It has now been convincingly demonstrated by human epidemiological investigations that the origins of many of the major chronic diseases that are manifest in adult life have their origins during development. Additionally, molecular, cellular and animal studies have now shown conclusively that interference with, or alteration of, developmental pathways during critical windows of development can provide the pathophysiological basis for the events that take place later in adult life. Our research attempts to answer the following: 1) differentiate the effects of fetal versus postnatal maternal dietary protein restriction on satellite cell accretion and skeletal muscle mass; 2) determine if impaired catch-up growth upon nutritional rehabilitation is due to aberrant epigenetic mechanisms intrinsic to the satellite cell and/or an absence of the extracellular cues necessary to sufficiently accelerate satellite cell division; 3) develop novel techniques to study amino acid metabolism in conscious mouse models, with special emphasis on hepatic and enteral metabolism; 4)determine the role of urea cycle intermediates in maintaining nitric oxide and ureagenesis during different physiological and pathophysiological conditions; 5) determine gene expression in human lactating mammary epithelium; 6) characterize inbred mouse strains for lactation performance, gene expression, and weight gain among offspring in lean and obese animals, making use of a cross-fostering design where appropriate; 7) study the effect of nutrients on mammary gland development and function in mouse models; define the critical window for effects on mammary gland development and function; 8) elucidate the role of vitamin A in vascular development and hematopoiesis using mouse embryos, in vitro assays, and complementary techniques; and 9) identify target genes downstream of retinoic acid signaling that are required for blood and blood vessel development.

1b. Approach (from AD-416):
These research studies will use various techniques to accomplish the research to be undertaken. Establishing the critical window of development during which an inadequate nutrient supply permanently compromises the growth of the skeletal muscle and to understand the responsible mechanisms is of great importance. Research studies will focus on the satellite cell in animal models in order to understand how the nutrition of the fetus and infant has lifelong consequences for the health of the individual. Studies will take place on the role of amino acids in the urea cycle (crucial for nitric oxide synthesis), which is in demand for physiological (growth, pregnancy) and pathophysiological (trauma, sepsis) conditions. Lactation research will be conducted in mouse models to obtain an improved understanding of the genomic factors regulating mammary gland function that is central to providing therapeutic interventions that can aid women to establish and maintain a productive lactation. Since the abnormal formation of blood and blood vessels in adults is central to the progression of prevalent pathologies, including atherosclerosis, tumor angiogenesis, and anemia, researchers will develop an understanding of the cellular and molecular regulation of blood and blood vessel formation. Scientists will study retinoids in their role in the formation and maturation of blood vessels, as well as hematopoiesis, during embryonic development. Additionally, CNRC researchers will investigate, on a cellular and molecular level, the role of retinoid signaling in the regulation of these processes.

3. Progress Report:
Significant research progress was accomplished during the year. To review the progress, please refer to project 6250-51000-054-10S (Project 1), 6250-51000-054-20S (Project 2), and 6250-51000-054-30S (Project 3).

4. Accomplishments
1. Finding the genes to turn on lactation. A lack of knowledge exists on the human genes that are turned on in the mammary epithelium (cells) at the time of delivery that result in the synthesis of lactose, the primary factor responsible for determining milk volume. Scientists at the Children's Nutrition Research Center in Houston, Texas, conducted studies using unique techniques of molecular biology to determine that the rate- limiting gene involved in the synthesis of lactose are the enzymes responsible for the formation of galactose and the induction of the prolactin receptor, which is a key hormonal factor in the initiation and sustaining of lactation in humans. By knowing the rate- limiting events in the process we may be able to create new therapies that might make the initiation of lactation more uniformly successful in the early hours after delivery. These findings could have an impact in humans and even into the induction of lactation in commercial animals.

2. variation exists for maternal nurturing ability in inbred mice. Although classical gene mapping approaches have identified quantitative trait loci (QTL) that may account for this variation, the underlying genes are unknown. Children's Nutrition Research Center researchers in Houston, Texas, performed a study in which lactation performance data was used to map genomic regions associated with this maternal nurturing variation. Our work identified up to 15 regions in the mouse genome containing 13 genes that were associated variations in maternal nurturing ability. Among the strongest candidate genes were a growth factor receptor, the epidermal growth factor receptor, a steroid hormone receptor, the mineralocorticoid receptor, and a GTP binding protein, Guanine nucleotide binding protein G(q). A comparison of these results with genomic variation in other species such as cows and humans would be expected to yield insights into the regulation of lactation in these species as well.

3. Hedgehog (Hh) signaling inhibits brown fat formation. Brown fat may have potential therapeutic benefits for preventing weight gain due to its function of burning calories to generate heat. Brown fat is formed during development under the control of a signaling network that is not yet well understood. By activating the Hh signaling pathway in developing brown fat tissue, Children's Nutrition Research Center researchers in Houston, Texas, discovered that high level of Hh signaling inhibits brown fat formation. Our studies, therefore, demonstrate a novel role for Hh signaling in the regulation of the brown fat cells.

Review Publications
Armstrong, J.J., Larina, I.V., Dickinson, M.E., Zimmer, W.E., Hirschi, K.K. 2010. Characterization of bacterial artificial chromosome transgenic mice expressing mCherry fluorescent protein substituted for the murine smooth muscle-alpha-actin gene. Genesis. 48:457-463.

Fouletier-Dilling, C., Wada, A.M., Lazard, Z.W., Salisbury, E.A., Gannon, F.H., Vadakkan, T.J., Gao, L., Hirschi, K., Dickinson, M.E., Davis, A.R., Olmsted-Davis, E.A. 2010. Vessel formation is induced prior to the appearance of cartilage in BMP-2-mediated heterotopic ossification. Journal of Bone and Mineral Research. 25(5):1147-1156.

Enciso, J.M., Konecny, C.M., Karpen, H.E., Hirschi, K.K. 2010. Endothelial cell migration during murine yolk sac vascular remodeling occurs by means of a Rac1 and FAK activation pathway in vivo. Developmental Dynamics. 239(10):2570-2583.

Kazanis, I., Lathia, J.D., Vadakkan, T.J., Raborn, E., Wan, R., Mughal, M.R., Eckley, D.M., Sasaki, T., Patton, B., Mattson, M.P., Hirschi, K.K., Dickinson, M.E., Ffrench-Constant, C. 2010. Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals. Journal of Neuroscience. 30(29):9771-9781.

Sivina, M., Yamada, T., Park, C.S., Puppi, M., Coskun, S., Hirschi, K., Lacorazza, H.D. 2011. The transcription factor E74-like factor controls quiescence of endothelial cells and their resistance to myeloablative treatments in bone marrow. Arteriosclerosis Thrombosis and Vascular Biology. 31(5):1185-1191.

Gazzaneo, M.C., Suryawan, A., Orellana, R.A., Torrazza, R.M., El-Kadi, S.W., Wilson, F.A., Kimbal, S.R., Srivastava, N., Nguyen, H.V., Fiorotto, M.L., Davis, T.A. 2011. Intermittent bolus feeding has a greater stimulatory effect on protein synthesis in skeletal muscle than continuous feeding in neonatal pigs. Journal of Nutrition. 141(12):2152-2158.

Motil, K. 2010. Developmental delay. In: Corkins, M.R., Balint J., Bobo E., Plogsted S., Yaworski J.A., editors. The ASPEN Pediatric Nutrition Support Core Curriculum. Silver Spring, MD: American Society for Paternal and Enteral Nutrition. p. 191-203.

Chaudhury, H., Raborn, E., Goldie, L.C., Hirschi, K.K. 2011. Stem cell-derived vascular endothelial cells and their potential application in regenerative medicine. Journal of Cells Tissues and Organs. 195(1-2):41-47.

Last Modified: 08/16/2017
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