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Research Project: Nutritional Metabolism in Mothers, Infants, and Children

Location: Children's Nutrition Research Center

2016 Annual Report

The overall goal of our research is to define the nutritional distresses and critical windows of development that alter physical activity (PA); understand the various factors that regulate mammary gland (MG) function in lactating mothers; and contribute to the development of nutritionally enhanced plant foods and assess their impact on human health. Specific objectives of this research include: 1) determine the effects of nutrition during critical window(s) of development on voluntary PA during late adolescence and middle age using mouse models; 2) determine the relative contributions of skeletal muscle mass, composition and contractile properties, exercise capacity, motor coordination, and behavior to the differences in voluntary PA induced by the nutritional perturbations incurred in early life; 3) determine the changes in gene and protein expression in skeletal and cardiac muscle and/or brain that contribute to the PA phenotypes induced by alterations in early life; 5) determine the compositional and molecular/genetic changes related to nutrients and bioactive phytochemicals in diverse bean varieties in response to elevated CO2 concentrations, intermittent drought and restricted potassium supply; 6) identify new genes required for calcium oxalate formation in Medicago truncatula; 7) identify genes required for calcium oxalate formation in Glycine max (soybean) and modify calcium oxalate content in Glycine max; 8) determine if microRNAs with plant-associated end chemistry can be functionally incorporated into a mammalian RNA-induced silencing complex/miRNA Ribonuclear Particle; 9) establish that food-associated microRNAs are present and functional in sera and tissues, and establish the relationship between dietary microRNA intake and metabolic changes; 10) determine the pathophysiology of lactation failure in obese women, including the role of progesterone, prolactin, and oxytocin in lactation in obese, as compared to normal weight women; 11) determine the importance of macrophage-mineralocorticoid receptor interaction to mammary gland development; and 12) determine in obese and non-obese lactating women, the relationship between obesity, and maternal oxytocin response during lactation, and breastfeeding success; we will also test whether maternal oxytocin response is positively associated with mother-infant sensitivity and brain reward response to infant face and cry cues using functional magnetic resonance imaging.

These research studies will use various techniques to accomplish the research to be undertaken. Complex and coordinated studies will be performed in mouse models to define the nutritional perturbations (over- and under-nutrition) and critical windows of development (pre- vs. postnatal) that alter physical activity in adulthood; define the type of activity that is altered; and elucidate the physiological basis for the observed changes. Obese and non-obese recent mothers will be recruited, studied, and recorded to evaluate hormone responses to breastfeeding, particularly to evaluate prolactin secretion and progesterone levels as well as oxytocin response variables. MRI scans will be used to evaluate the activation of dopamine-associated brain reward regions in response to seeing own vs. unknown infant face cues. Additionally mice will be utilized to determine if ablation of macrophages during late pregnancy in obese mice will restore milk production and allow for the support of normal weight gain in cross-fostered litters; and we will attempt to understand how stem and progenitor cells are affected by obesity that lead to altered lactation capacity. To ensure an optimal food supply in the future, work will focus on characterizing how elevated CO2, intermittent drought, or a restricted supply of potassium may impact concentrations of certain minerals, protein, and bioactive phytochemicals in seed or edible vegetative plant tissues. Genome-wide association analysis will be employed to identify genomic loci associated with altered nutritional traits. We will also identify the plant genes that synthesize oxalate and calcium oxalate, and this information will be used to design strategies to manipulate oxalate content in important food plants (such as soybean) for the purpose of improving nutritional quality. Finally, experiments will be conducted to determine whether food-associated plant microRNAs are present and functional in sera and tissues, and to establish the relationship between dietary microRNA intake and metabolic changes.

Progress Report
Significant research progress was accomplished during the year. To review the progress, please refer to project 3092-51000-056-01S (Project #1), 3092-51000-056-02S (Project #2), and 3092-51000-056-03S (Project #3).

1. Postnatal undernutrition permanently impairs cardiac function. Individuals who were born small or have poor growth early in life are at an increased risk of developing heart disease as adults but why this is the case is unknown. Scientists at the Children's Nutrition Research Center in Houston, Texas attempted to replicate this in a mouse model to determine what is responsible for the defect and how it affects physical activity in adulthood. Our results showed that a brief period of undernutrition during a critical stage of development results in changes in heart function that persist throughout the lifespan and that these consequences are manifested when the heart is under stress. This information is important because it identifies individuals who could be at increased risk for cardiovascular events when they engage in strenuous activities.

2. Building calcium oxalate crystals in plants to deter insects. Insects directly impact agricultural plant production by chewing plant leaves, boring within the leaves and other plant parts, and a variety of other mechanisms, all of which create economic losses for producers. Researchers are interested in transferring the mechanisms that some plants use to build calcium oxalate crystals (a physical deterrent to some chewing insects) into plants that do not naturally possess this ability to generate these crystals. Research conducted at the Children's Nutrition Research Center in Houston, Texas has shown that building crystals in plants that do not normally make these crystals is possible; however there are some negative consequences, such as slower plant growth and altered leaf appearance. Future work will be required to alleviate these negative consequences before crystal building can be used as a new non-pesticide means of protecting plants against chewing insects.

3. Why are plant diets healthy? Researchers believe that plant genetic information may be an unappreciated component that may impact consumer wellbeing. Can consumption of common vegetables provide unique dietary genetic information to consuming animals? Researchers at the Children's Nutrition Research Center in Houston, Texas conducted experiments in animal models and found that diets high in broccoli or cabbage deliver high levels of plant-specific genetic information to the blood stream of consuming animals. This finding alters researcher's perception of how plants impact health and provides a preliminary outline for dietary based gene therapies.

4. Dry bean nutritional quality in the face of drought. Climate change phenomena have been shown to impact the nutritional quality of some crop plants. Children's Nutrition Research Center researchers in Houston, Texas, in cooperation with multi-site collaborators, grew a diverse set of bean cultivars at field sites maintained under controlled conditions (adequate moisture or drought conditions) and analyzed seeds for mineral concentrations and yield at harvest. While the yield was reduced under drought relative to control conditions, mineral concentrations were not reduced by drought. These results demonstrate that in the face of reduced seed productivity, the mineral nutritional quality of the beans produced is not affected.

Review Publications
Hu, Y., Wu, Q., Sprague, S.A., Park, J., Oh, M., Rajashekar, C.B., Koiwa, H., Nakata, P.A., Cheng, N., Hirschi, K., White, F.F., Park, S. 2015. Tomato expressing Arabidopsis glutaredoxin gene AtGRXS17 confers tolerance to chilling stress via modulating cold responsive components. Horticulture Research. 2: 15051.
Nakata, P.A. 2015. An assessment of engineered calcium oxalate crystal formation on plant growth and development as a step toward evaluating its use to enhance plant defense. PLoS One. 10(10):e0141982.
Schaeffer, S.M., Nakata, P.A. 2015. CRISPR/Cas9 mediated genome editing and gene insertion in plants: Transitioning from lab to field. Plant Science. 240:130-142.
Narayanan, N., Beyene, G., Chauhan, R., Gaitan-Solis, E., Grusak, M.A., Taylor, N., Anderson, P. 2015. Overexpression of Arabidopsis VIT1 increases accumulation of iron in cassava roots and stems. Plant Science. 240: 170-181.
Foster, J., Luo, B., Nakata, P.A. 2016. An oxalyl-CoA dependent pathway of oxalate catabolism plays a role in regulating calcium oxalate crystal accumulation and defending against oxalate-secreting phytopathogens in Medicago truncatula. PLoS One. 11(2):e0149850.
Gaxiola, R.A., Regmi, K., Hirschi, K.D. 2016. Moving on up: H(+)-PPase mediated crop improvement. Trends in Biotechnology. 34(5):347-349.
Pittman, J.K., Hirschi, K.D. 2016. CAX-ing a wide net: Cation/H(+) transporters in metal remediation and abiotic stress signalling. Plant Biology. doi:10.1111/plb.12460.
Yang, J., Hotz, T., Broadnax, L., Yarmarkovich, M., Elbaz-Younes, I., Hirschi, K.D. 2016. Anomalous uptake and circulatory characteristics of the plant-based small RNA MIR2911. Scientific Reports. 6(26834):1-9. doi:10.1038/srep26834.
Zhao, J., Li, P., Motes, C.M., Park, S., Hirschi, K.D. 2015. CHX14 is a plasma membrane K-efflux transporter that regulates K+ redistribution in "Arabidopsis thaliana". Plant, Cell & Environment. 38(11):2223-2238.
Thompson, S.M., Hirschi, K.D. 2016. 605 Salad crops: Root, bulb, and tuber crops. In: Caballero, B., Finglas, P.M., and Toldra, F., editors. Encyclopedia of Food and Health. Waltham, MA: Academic Press. p. 679-684.
Wooten-Kee, C.R., Jain, A.K., Wagner, M., Grusak, M.A., Finegold, M.J., Lutsenko, S., Moore, D.D. 2015. Elevated copper impairs hepatic nuclear receptor function in Wilson's disease. Journal of Clinical Investigation. 125(9):3449-3460.
Cheng, P., Holdsworth, W., Ma, Y., Coyne, C.J., Mazourek, M., Grusak, M.A., Fuchs, S., Mcgee, R.J. 2015. Phylogenetic analysis and association mapping for agronomic and quality traits in the USDA pea single-plant collection. Molecular Breeding. 35:75. doi: 10.1007/s11032-015-0277-6.
Guitierrez-Carbonell, E., Lattanzio, G., Albacete, A., Rios, J.J., Kehr, J., Abadia, A., Grusak, M.A., Abadia, J., Lopez-Millan, A.F. 2015. Effects of Fe deficiency on the protein profile of Brassica napus phloem sap. Proteomics. 15(22):3835-3853.
Goodyear, A., Ehrhart, E.J., Swanson, K.S., Grusak, M.A., Leach, J.E., Dow, S.W., McClung, A.M., Ryan, E. 2015. Dietary rice bran supplementation prevents salmonella colonization differentially across varieties and by priming intestinal immunity. Journal of Functional Foods. 18:653-664.
Jimenez-Aguilar, D.M., Grusak, M.A. 2015. Evaluation of minerals, phytochemical compounds and antioxidant activity of Mexican, Central American, and African green leafy vegetables. Plant Foods for Human Nutrition. 70:357-364.
Traber, M.G., Leonard, S.W., Bobe, G., Fu, X., Saltzman, E., Grusak, M.A., Booth, S.L. 2015. Alpha-tocopherol disappearance rates from plasma depend on lipid concentrations: Studies using deuterium labeled collard greens in younger and older adults. American Journal of Clinical Nutrition. 101(4):752-759.
Rodriguez-Celma, J., Ceballos-Laita, L., Grusak, M.A., Abadia, J., Lopez-Millan, A.F. 2016. Plant fluid proteomics: Delving into the xylem sap, phloem sap and apoplastic fluid proteomes. Biochimica et Biophysica Acta. 1864(8):991-1002.
Christiansen, J.S., Backeljauw, P.F., Bidlingmaier, M., Biller, B.M., Boguszewski, M.C., Casanueva, F.F., Chanson, P., Chatelain, P., Choong, C.S., Clemmons, D.R., Cohen, L.E., Cohen, P., Frystyk, J., Grimberg, A., Hasegawa, Y., Haymond, M.W., Ho, K., Hoffman, A.R., Holly, J.M., Horikawa, R., Höybye, C., Jorgensen, J.O., Johannsson, G., Juul, A., Katznelson, L., Kopchick, J.J., Lee, K.O., Lee, K.W., Luo, X., Melmed, S., Miller, B.S., Misra, M., Popovic, V., Rosenfeld, R.G., Ross, J., Ross, R.J., Saenger, P., Strasburger, C.J., Thorner, M.O., Werner, H., Yuen, K. 2016. Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations. European Journal of Endocrinology. 174(6):1-8. doi: 10.1530/EJE-16-0111.
Allen, D.B., Backeljauw, P.F., Bidlingmaier, M., Biller, B.B., Boguszewski, M., Burman, P., Butler, G., Chihara, K., Christiansen, J., Cianfarani, S., Clayton, P., Clemmons, D., Cohen, P., Darendeliler, F., Deal, C., Dunger, D., Erfurth, E.M., Fuqua, J.S., Grimberg, A., Haymond, M.W., Higham, C., Ho, K., Hoffman, A.R., Hokken-Koelega, A., Johannsson, G., Juul, A., Kopchick, J., Lee, P., Pollak, M., Radovick, S., Robison, L., Rosenfeld, R., Ross, R.J., Savendahl, L., Saenger, P., Toft Sorensen, H., Stochholm, K., Strasburger, C., Swerdlow, A., Thorner, M. 2015. GH safety workshop position paper: A critical appraisal of recombinant human GH therapy in children and adults. European Journal of Endocrinology. 174(2):1-9.
Chung, S.T., Chacko, S.K., Sunehag, A.L., Haymond, M.W. 2015. Measurements of gluconeogenesis and glycogenolysis: A methodological review. Diabetes. 64:3996-4010.
Haymond, M.W., Redondo, M.J., Mckay, S., Cummins, M.J., Newswanger, B., Kinzell, J., Prestrelski, S. 2016. Nonaqueous, mini-dose glucagon for treatment of mild hypoglycemia in adults with type 1 diabetes: A dose-seeking study. Diabetes Care. 39(3):465-468.
Nichols, B.L., Diaz-Sotomayor, M., Avery, S.E., Chacko, S.K., Hadsell, D.L., Baker, S.S., Hamaker, B.R., Yan, L.K., Lin, H.M., Quezada-Calvillo, R. 2016. Milk glucosidase activity enables suckled pup starch digestion. Molecular and Cellular Pediatrics. doi:10.1186/s40348-016-0032-z.
Schaeffer, S.M., Nakata, P.A. 2016. The expanding footprint of CRISPR/Cas9 in the plant sciences. Plant Cell Reports. 35(7):1451-1468.
Pittman, J.K., Hirschi, K.D. 2016. Phylogenetic analysis and protein structure modelling identifies distinct Ca(2+)/Cation antiporters and conservation of gene family struucture within Arabidoposis and rice species. Rice. 9(1)3:1-6.