MAGNETIC RESONANCE AND DIFFUSION TENSOR IMAGING OF A MOUSE FASD MODEL U01
Kathleen Sulik, Professor
Cell Biology And Anatomyuniversity Of North Carolina Chapel Hill
Grant 5U01AA017124-02 from National Institute On Alcohol Abuse And Alcoholism, IRG: ZAA1
Abstract: Fetal Alcohol Spectrum Disorders (FASD), significant components of which are Central Nervous System (CMS) and craniofacial abnormalities, are a major public health problem. While eliminating FASD is the ultimate goal for both clinical and basic FASD research, we recognize that in the near future, adverse effects from prenatal ethanol exposure will persist. To better diagnose and treat affected individuals, a more complete understanding of the full spectrum of the ethanol-induced abnormalities is needed. The proposed investigations are designed to integrate with those of other consortium members in meeting this need. For this work, both high resolution Magnetic Resonance Imaging (MRI), which can provide 29 micron (or less) isotropic scans and subsequent accurate 3-D reconstructions and segmental analyses, and Diffusion Tensor Imaging (DTI), which allows CMS fiber tract analyses, will be applied to the study of an FASD mouse model. Previous research utilizing this model has established critical exposure times that yield facial and CNS abnormalities that are consistent with full-blown Fetal Alcohol Syndrome, as well as other components of FASD. The proposed studies will employ this model and both acute and chronic ethanol treatment paradigms to test the overall hypothesis that in mice, ethanol induces structural abnormalities of the brain and face that are consistent with and informative for those in human FASD. To this end, utilizing MRI and DTI as high throughput screening platforms, we propose to address the following specific aims 1) to provide comprehensive documentation and discovery of the ethanol-induced CNS dysmorphology that results from prenatal ethanol exposure at embryonic and early fetal stages of development; 2) to define the facial dysmorphology that results from prenatal ethanol exposure during embryonic and/or early fetal stages and to relate their character and severity to accompanying abnormalities of the brain; and 3) to identify regions other than the brain or face that may serve as diagnostic indicators of prenatal ethanol exposure. The results of the proposed studies will be compared to those of corresponding investigations by other consortium members. It is expected that the structural abnormalities of the brain and face that are induced by ethanol in mice will reflect the pattern of defects observed in children with FASD, will inform human diagnostic tests, and will provide new information that will be helpful in reducing the incidence of FASD
Keywords: congenital oral /facial /cranial defect, diffusion magnetic resonance imaging, ethanol, fetal alcohol syndrome, magnetic resonance imaging, morphology disease /disorder model, embryo /fetus toxicology, environmental exposure, growth /development bioimaging /biomedical imaging, laboratory mouse
Project start date: 2007-09-30
Project end date: 2012-07-31
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Grants awarded to Kathleen Sulik
MAGNETIC RESONANCE AND DIFFUSION TENSOR IMAGING OF A MOUSE FASD MODEL U01
Kathleen Sulik, Professor
Cell Biology And Anatomyuniversity Of North Carolina Chapel Hill
Grant 5U01AA017124-02 from National Institute On Alcohol Abuse And Alcoholism, IRG: ZAA1
Abstract: Fetal Alcohol Spectrum Disorders (FASD), significant components of which are Central Nervous System (CMS) and craniofacial abnormalities, are a major public health problem. While eliminating FASD is the ultimate goal for both clinical and basic FASD research, we recognize that in the near future, adverse effects from prenatal ethanol exposure will persist. To better diagnose and treat affected individuals, a more complete understanding of the full spectrum of the ethanol-induced abnormalities is needed. The proposed investigations are designed to integrate with those of other consortium members in meeting this need. For this work, both high resolution Magnetic Resonance Imaging (MRI), which can provide 29 micron (or less) isotropic scans and subsequent accurate 3-D reconstructions and segmental analyses, and Diffusion Tensor Imaging (DTI), which allows CMS fiber tract analyses, will be applied to the study of an FASD mouse model. Previous research utilizing this model has established critical exposure times that yield facial and CNS abnormalities that are consistent with full-blown Fetal Alcohol Syndrome, as well as other components of FASD. The proposed studies will employ this model and both acute and chronic ethanol treatment paradigms to test the overall hypothesis that in mice, ethanol induces structural abnormalities of the brain and face that are consistent with and informative for those in human FASD. To this end, utilizing MRI and DTI as high throughput screening platforms, we propose to address the following specific aims 1) to provide comprehensive documentation and discovery of the ethanol-induced CNS dysmorphology that results from prenatal ethanol exposure at embryonic and early fetal stages of development; 2) to define the facial dysmorphology that results from prenatal ethanol exposure during embryonic and/or early fetal stages and to relate their character and severity to accompanying abnormalities of the brain; and 3) to identify regions other than the brain or face that may serve as diagnostic indicators of prenatal ethanol exposure. The results of the proposed studies will be compared to those of corresponding investigations by other consortium members. It is expected that the structural abnormalities of the brain and face that are induced by ethanol in mice will reflect the pattern of defects observed in children with FASD, will inform human diagnostic tests, and will provide new information that will be helpful in reducing the incidence of FASD
Keywords: congenital oral /facial /cranial defect, diffusion magnetic resonance imaging, ethanol, fetal alcohol syndrome, magnetic resonance imaging, morphology disease /disorder model, embryo /fetus toxicology, environmental exposure, growth /development bioimaging /biomedical imaging, laboratory mouse
Project start date: 2007-09-30
Project end date: 2012-07-31
Kathleen Sulik
University Of North Carolina Chapel Hill
office Of Sponsored Research
chapel Hill, Nc 27599
Grant 2P60AA011605-116288 from National Institute On Alcohol Abuse And Alcoholism, IRG: ZAA1
Related Publications
Nrf2-mediated transcriptional induction of antioxidant response in mouse embryos exposed to ethanol in vivo: implications for the prevention of fetal alcohol spectrum disorders. Antioxid Redox Signal. 2008 Dec; 10( 12): 2023-33. PMID: 18759561 Concurrent dietary administration of D-SAL and ethanol diminishes ethanol's teratogenesis. Alcohol Clin Exp Res. 2007 Dec; 31( 12): 2059-64. Epub 2007 Oct 19. PMID: 17949468 Perturbation of retinoic acid (RA)-mediated limb development suggests a role for diminished RA signaling in the teratogenesis of ethanol. Birth Defects Res A Clin Mol Teratol. 2007 Sep; 79( 9): 631-41. PMID: 17676605 
Reprogramming of genetic networks during initiation of the Fetal Alcohol Syndrome. Dev Dyn. 2007 Feb; 236( 2): 613-31. PMID: 17200951 Maternal oral intake mouse model for fetal alcohol spectrum disorders: ocular defects as a measure of effect. Alcohol Clin Exp Res. 2006 Oct; 30( 10): 1791-8. PMID: 17010146 Novel role for the orphan nuclear receptor Dax1 in embryogenesis, different from steroidogenesis. Mol Genet Metab. 2006 Jul; 88( 3): 261-71. Epub 2006 Feb 8. PMID: 16466956 Genesis of alcohol-induced craniofacial dysmorphism. Exp Biol Med (Maywood). 2005 Jun; 230( 6): 366-75. Review. PMID: 15956766 Peptide-mediated protection from ethanol-induced neural tube defects. Dev Neurosci. 2005 Jan-Feb; 27( 1): 13-9. PMID: 15886480 Protection from ethanol-induced limb malformations by the superoxide dismutase/catalase mimetic, EUK-134. FASEB J. 2004 Aug; 18( 11): 1234-6. Epub 2004 Jun 18. PMID: 15208273 Ethanol antagonist peptides: structural specificity without stereospecificity. J Pharmacol Exp Ther. 2004 Jun; 309( 3): 1183-9. Epub 2004 Feb 4. PMID: 14762101 
An atlas of gastrointestinal embryology. Am J Med Genet A. 2003 Nov 1; 122A( 4): 283-6. No abstract available. PMID: 14518064 
Differential effects of ethanol antagonism and neuroprotection in peptide fragment NAPVSIPQ prevention of ethanol-induced developmental toxicity. Proc Natl Acad Sci U S A. 2003 Jul 8; 100( 14): 8543-8. Epub 2003 Jun 13. PMID: 12808140 Hindbrain and cranial nerve dysmorphogenesis result from acute maternal ethanol administration. Dev Neurosci. 2002; 24( 4): 328-42. PMID: 12457071 Distinct requirements for extra-embryonic and embryonic bone morphogenetic protein 4 in the formation of the node and primitive streak and coordination of left-right asymmetry in the mouse. Development. 2002 Oct; 129( 20): 4685-96. PMID: 12361961 exma: an X-linked insertional mutation that disrupts forebrain and eye development. Mamm Genome. 2002 Apr; 13( 4): 179-85. PMID: 11956759