YEARS

2002-2008

AUTHORS

Mary Renee Prater

TITLE

IMMUNE PROTECTION AGAINST MNU-INDUCTED DIGITAL DEFECTS

ABSTRACT

DESCRIPTION (Provided by applicant): 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.

FUNDED PUBLICATIONS

  • Production of a type 2 maternal diabetes rodent model using the combination of high-fat diet and moderate dose of streptozocin.
  • Does immune stimulation or antioxidant therapy reduce MNU-induced placental damage via activation of Jak-STAT and NFkappaB signaling pathways?
  • Prebreeding maternal immunostimulation with Freund's complete adjuvant reduces placental damage and distal limb defects caused by methylnitrosourea.
  • Late-gestation ventricular myocardial reduction in fetuses of hyperglycemic CD1 mice is associated with increased apoptosis.
  • Reduced birth defects caused by maternal immune stimulation in methylnitrosourea-exposed mice: association with placental improvement.
  • Placental oxidative stress alters expression of murine osteogenic genes and impairs fetal skeletal formation.
  • Role of maternal dietary antioxidant supplementation in murine placental and fetal limb development.
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    1 grants:cad7215c3f02c2a8b546760c62aa4164 sg:abstract DESCRIPTION (Provided by applicant): 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.
    2 sg:endYear 2008
    3 sg:fundingAmount 534128.0
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    19 sg:scigraphId cad7215c3f02c2a8b546760c62aa4164
    20 sg:startYear 2002
    21 sg:title IMMUNE PROTECTION AGAINST MNU-INDUCTED DIGITAL DEFECTS
    22 sg:webpage http://projectreporter.nih.gov/project_info_description.cfm?aid=7039120
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    24 rdfs:label Grant: IMMUNE PROTECTION AGAINST MNU-INDUCTED DIGITAL DEFECTS
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