Dr. Renee Prater has completed her D.V.M., M.S. in physiology, residency in clinical pathology, and is a Ph.D. candidate in toxicology with an expected completion date of 12/2001. She is a highly motivated scientist who sees this award as an opportunity to advance her research career as an independent primary investigator in developmental immunotoxicology. The proposed research will investigate mechanisms by which maternal immune stimulation prevents methylnitrosourea (MNU)-induced birth defects. MNU's teratogenic effects are dose-specific and dependent upon the time of exposure in relation to gestational age. Organ systems affected by MNU include the central nervous, lymphoid, digestive, genitourinary, and limbs. Data from the laboratory have demonstrated that nonspecific activation of the murine maternal immune system can dramatically reduce several chemical-induced birth defects, including MNU-induced digital defects (DDs), and that maternal immune stimulation normalizes teratogen-altered expression of fetal regulatory genes in palatal development. Other investigators have reported that altered gene expression in MNU-induced teratogenesis can be normalized with dietary antioxidant supplementation (Hulten et al. 1998). A focused examination of altered gene expression and protection from MNU-induced DD is now logical. Specifically, the following hypotheses will be tested: 1) MNU affects gene expression regulating digital development; 2) maternal immune stimulation normalizes gene expression through regulatory proteins secreted by activated immune cells, and 3) protection from MNU-induced digital defects can also result from dietary supplementation with the antioxidant butylated hydroxytoluene (BHT) in a process involving similar effects on regulatory genes. These studies are expected to significantly increase our 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 will improve the understanding of this disorder and contribute to means for prevention or cure. This research under the guidance of Drs. Steven Holladay and Eric Wong at Virginia Tech.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01RR017018-05
Application #
7039120
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Watson, William T
Project Start
2002-04-01
Project End
2008-07-31
Budget Start
2006-04-01
Budget End
2008-07-31
Support Year
5
Fiscal Year
2006
Total Cost
$114,576
Indirect Cost
Name
Virginia Polytechnic Institute and State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
003137015
City
Blacksburg
State
VA
Country
United States
Zip Code
24061
Gutierrez, J Claudio; Bahamonde, Javiera; Prater, M Renee et al. (2010) Production of a type 2 maternal diabetes rodent model using the combination of high-fat diet and moderate dose of streptozocin. Endocr Res 35:59-70
Gutierrez, J Claudio; Prater, M Renee; Smith, Bonnie J et al. (2009) Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis. Birth Defects Res B Dev Reprod Toxicol 86:409-15
Prater, M R; Laudermilch, C L; Liang, C et al. (2008) Placental oxidative stress alters expression of murine osteogenic genes and impairs fetal skeletal formation. Placenta 29:802-8
Prater, M R; Laudermilch, C L; Holladay, S D (2007) Does immune stimulation or antioxidant therapy reduce MNU-induced placental damage via activation of Jak-STAT and NFkappaB signaling pathways? Placenta 28:566-70
Renee Prater, Mary; Zimmerman, Kurt L; Laudermilch, Chelsea L et al. (2006) Prebreeding maternal immunostimulation with Freund's complete adjuvant reduces placental damage and distal limb defects caused by methylnitrosourea. Am J Reprod Immunol 55:145-55
Prater, M R; Zimmerman, K L; Pinn, L C et al. (2006) Role of maternal dietary antioxidant supplementation in murine placental and fetal limb development. Placenta 27:502-9
Prater, Mary Renee; Zimmerman, Kurt Lee; Ward, Daniel Lee et al. (2004) Reduced birth defects caused by maternal immune stimulation in methylnitrosourea-exposed mice: association with placental improvement. Birth Defects Res A Clin Mol Teratol 70:862-9