Autism is a neuro-developmental disorder with several known environmental and genetic risk factors. Converging evidence from anatomical studies, teratologic studies, and studies of comorbid conditions suggest that one cause of autism is early maldevelopment of the brain stem. Evidence for several new candidate genes for ASD susceptibility has been published in the last year, and all are genes involved in the embryonic development of the brain stem. In Project I, Animal Models of Autism and Mechanisms of Injury, the investigators will study the neuroanatomy of animal models and quantify gene expression in embryos exposed to teratogens, using real-time PCR and in situ hybridization. They propose to extend out studies of the mechanisms of action of teratogens associated with autism to investigate the role of histone deacetylation. The investigators will compare transcription efficacy of polymorphisms of genetic susceptibility factors in TET-responsive cell lines, and look for gene-environment interactions in genetically-engineered mice exposed to teratogens in utero. The goal is to understand how teratologic agents and genetic anomalies produce similar effects on the hindbrain. Project II. Behaviors Discriminating Autism in Humans and Animals, is an investigation of behavioral tasks with promise to discriminate autism from other developmental disabilities. The goal is to develop animal tasks that can serve as markers of the developmental abnormalities that cause autism so that animal models like those developed in Project I can be tested for parallelism to the human disorder. Inhibition of return and eyeblink conditioning are the tasks under study in this application. Project III, Genotype and Phenotype in Autism and Behaviorally-Related Disorders, has assessed behavioral symptomatology, minor physical anomalies, neurological / ophthalmological deficits, and mutations of early developmental genes in four groups with developmental disabilities (autism, Asperger syndrome, M?bius syndrome, and language disorder) and controls with typical development. The investigators propose to add two groups - children with autism and mental retardation and IQ-matched controls. The goal is to determine whether the phenotypic or genotypic features of these disorders indicate common etiologies. Project IV, Gene-Environment Interactions in three Populations Exposed to Teratogens Associated with Autism, will examine six suspected genetic susceptibility factors in people exposed in utero to three teratogens known to be associated with autism: thalidomide, valproic acid, and misoprostol. The investigators propose to determine whether the members of these populations who meet diagnostic criteria for ASDs are ones with genetic risk factors. This project is closely related to the gene-environment studies proposed in animals.
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| Arndt, Tara L; Stodgell, Christopher J; Rodier, Patricia M (2005) The teratology of autism. Int J Dev Neurosci 23:189-99 |
| Stromland, Kerstin; Sjogreen, Lotta; Johansson, Maria et al. (2005) CHARGE association in Sweden: malformations and functional deficits. Am J Med Genet A 133A:331-9 |
| Martinez-Ceballos, Eduardo; Chambon, Pierre; Gudas, Lorraine J (2005) Differences in gene expression between wild type and Hoxa1 knockout embryonic stem cells after retinoic acid treatment or leukemia inhibitory factor (LIF) removal. J Biol Chem 280:16484-98 |
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| Levy, Susan E; Hyman, Susan L (2005) Novel treatments for autistic spectrum disorders. Ment Retard Dev Disabil Res Rev 11:131-42 |
| Miller, Marilyn T; Stromland, Kerstin; Ventura, Liana et al. (2005) Autism associated with conditions characterized by developmental errors in early embryogenesis: a mini review. Int J Dev Neurosci 23:201-19 |
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