Mouse models for the identification of neural tube defect etiologies : a dissertation /
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| Format: | Thesis Book |
| Language: | English |
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[College Station, Tex.] :
[Texas A&M University System Health Science Center],
[2006]
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| Abstract: | ABSTRACTS: Neural tube defects (NTDs) are serious malformations affecting approximately 1 per 1000 births, affectively making NTDs the second most common type of human congenital abnormality. Clinical trials on women of childbearing age have demonstrated that folic acid supplementation can decrease the occurrence of NTDs by up to 70 percent. In order to study how folates reduce the occurrence of neural tube defects, the folate binding protein 1 (Folbp1) gene was inactivated in mice. Nullizygous embryos (Folbp1⁻/⁻) have significant malformations of the neural tube and craniofacies and invariably die in utero by gestational day 10. Folate supplementation enables a proportion of the embryos to survive, but they present with anterior NTDs. In response to higher concentrations of supplemental folate, the mice exhibit normal phenotypes. Folate responsive gene expression changes following folate supplementation were identified. The analyses indicate that folates induce the expression of methyltransferases. Two different inbred Folbp1 knockout strains were established and used to determine the effect of genetic backgrounds on the penetrance of Folbp1⁻/⁻ associated NTDs. Strain background was determined to be a major modifier for risk of NTDs in Folbp1⁻/⁻ mice. A test for autoantibodies, which can be produced by disruption of an identified downstream methyltransferase, was developed. Results indicate that antibodes to exogenous folate binding protein can produce NTDs in mice. This work has thereby demonstrated that folic acid supplementation induces specific changes in gene expression cascades, which function at the level of protein methylation, and the inhibition or inactivation of these methyltransferases has been shown to disrupt oncogenic and cytoskeletal protein localization and is associated with the production of autoantibodies and NTDs. Further understanding of normal development and how chemicals can perturb these orchestrated processes was also investigated by the use of the antiepileptic medication, valproate (valproic acid, VPA). Gene expression changes following exposure to teratogenic concentrations of VPA were identified in association with embryonic delays in somite development. The composite of these results provides insight into two important mouse models of NTDs, and the conclusion of this dissertation addresses the NTD etiologies of these models in relation to human NTDs. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". "Submitted to the Graduate School of Biomedical Sciences of The Texas A&M University System Health Science Center in partial fulfillment for the requirements for the degree of Doctor of Philosophy May 2006." Approved as to style and content by: Richard H. Finnell, James F. Martin, Robert J. Schwartz, Richard R. Sinden, Eric L. Brown. |
| Physical Description: | xi, 158 leaves : illustrations ; 28 cm. |
| Bibliography: | Includes bibliographical references (leaves 136-154). |