Dr. Terry Hrubec received the D.V.M. and Ph.D. degrees and is embarking on a research career. She is a highly motivated scientist who wishes to make a career shift from clinical pathology and immunology of aquatic species to research in mammalian cellular and molecular immunology. This award would offer Dr. Hrubec an opportunity to strengthen and expand research skills by affording training in molecular mechanisms of developmental abnormalities and using animal models of human disease. The proposed research investigates the mechanism by which maternal immune stimulation prevents valproic acid (VA) induced birth defects. VA, a drug commonly used to treat epilepsy, is teratogenic and induces neural tube defects (NTDs) in one to two percent of exposed fetuses at a rate 20 times higher than in the general population. In what the investigators feel is paradigm-changing work, data from the investigators' laboratory have conclusively demonstrated that non-specific activation of the maternal immune system in rodents can dramatically reduce a variety of chemical-induced birth defects, including VA induced NTDs. Additionally, the investigators have shown that such maternal immune stimulation normalizes teratogen-altered expression of a few selected fetal cell-cycle/apoptotic regulatory genes in urethane-induced cleft palate. A more focused examination of altered gene expression in VA induced NTDs is now logical. Specifically, the investigators will test the hypotheses that: 1) VA affects the expression of genes regulating neural tube development, and that maternal immune stimulation normalizes gene expression through regulatory proteins (cytokines) secreted by activated immune cells; and 2) folic acid supplementation protects against NTDs by cytokine-related mechanisms which may in part be similar to that resulting after maternal immune stimulation. These studies are expected to significantly increase the investigators' understanding of genetic mechanisms by which maternal immune modulation reduces this specific birth defect. Clearly, this research is of importance to human health, as determining the mechanisms involved will improve the understanding of this disorder leading to a prevention or cure. This research will be conducted under the guidance of Drs. Steven Holladay and Ansar Ahmed of the Virginia-Maryland Regional College of Veterinary Medicine at the VPISU, and will offer excellent training and career development for Dr. Hrubec.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Research Scientist Development Award - Research & Training (K01)
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National Center for Research Resources Initial Review Group (RIRG)
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Harding, John D
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Virginia Polytechnic Institute and State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Mallela, Mural; Hrubec, Theresa (2012) Reduction in valproic acid-induced neural tube defects by maternal immune stimulation: role of apoptosis. Birth Defects Res B Dev Reprod Toxicol 95:296-303
Mallela, Murali K; Werre, Stephen R; Hrubec, Terry C (2011) Neural tube defects in mice exposed to tap water. Environ Toxicol 26:633-40
Hrubec, Terry C; Toops, Kimberly A; Holladay, Steven D (2009) Modulation of diabetes-induced palate defects by maternal immune stimulation. Anat Rec (Hoboken) 292:271-6
Hrubec, Terry C; Yan, Mingjin; Ye, Keying et al. (2006) Valproic acid-induced fetal malformations are reduced by maternal immune stimulation with granulocyte-macrophage colony-stimulating factor or interferon-gamma. Anat Rec A Discov Mol Cell Evol Biol 288:1303-9
Hrubec, Terry C; Prater, M Renee; Toops, Kimberly A et al. (2006) Reduction in diabetes-induced craniofacial defects by maternal immune stimulation. Birth Defects Res B Dev Reprod Toxicol 77:1-9