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Defining the Molecular Origins of Developmental Brain Disorders

定义大脑发育障碍的分子起源

基本信息

批准号：
9332052
负责人：
Andy Madrid
金额：
$ 3.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9332052
关键词：
Adult Antibodies Anxiety Autistic Disorder Behavior Behavioral Binding Biological Assay Brain Brain Diseases Cells Complex Corpus striatum structure DNA Methylation DNA Modification Process DNA Sequence Alteration Data Development Diagnosis Disease Dose Embryo Epigenetic Process Etiology Exhibits Female GABA Receptor Gene Expression Gene Expression Regulation Genes Genetic Predisposition to Disease Genetic Transcription Genome Genomics Hereditary Disease Heterozygote Homozygote Human Lead Life Link Mediating Mental Depression Mental Health Mental disorders Methods Mitotic Modification Molecular Molecular Target Mus Mutant Strains Mice Mutation Neurons Nuclear Nucleotides Orthologous Gene Outcome Oxytocin Pathogenesis Pathway interactions Phenotype Physiological Psyche structure RNA Reporting Role Schizophrenia Signal Transduction Social Behavior Social Interaction Stress Testing Tissues Training Transcript Western Blotting autism spectrum disorder crosslink effective therapy gene environment interaction genome-wide genomic profiles mouse model mutant neglect nervous system disorder novel prenatal prenatal stress public health relevance response social stressor transcription factor

项目摘要

PROJECT SUMMARY / ABSTRACT Only a small percentage of the autism spectrum disorders appear to have a clear genetic etiology (~25%), leaving a majority of cases with unclear origins. Alterations in environmentally sensitive epigenetic marks (e.g., DNA methylation) have been implicated in mental illness, including autism. A novel epigenetic mark, 5- hydroxymethylcytosine (5hmC), is enriched in neurons and is associated with active transcription of neuronal genes. While numerous studies have profiled 5hmC and found links to neurological disorders, less effort has been invested in determining the functional role of 5hmC, as it pertains to gene expression. As a result, the full functional potential of 5hmC modifications has yet to be realized in outcomes related to behavior. A recent genome-wide profile of striatal 5hmC in an autism mouse model (i.e., a Cntnap2-/- homozygote) that exhibits core autism features, including deficits in striatal GABAergic signaling, revealed a genome-wide disruption of 5hmC in the orthologs of a remarkable number of genes implicated in human autism (N=68/233). Thus, these data suggest a role for 5hmC-mediated epigenetic modulation in the pathogenesis of autism and represent a critical step toward understanding the genome-wide molecular consequences of a homozygous mutation that results in an autism-like phenotype. Notably, Cntnap2+/- heterozygous mutant mice lack autistic-like features. Since 5hmC levels are environmentally sensitive, these findings led to the hypothesis that Cntnap2+/- heterozygous mice subjected to an early environmental stress would have disruptions in 5hmC and may exhibit autistic-like behaviors similar to the Cntnap2-/- homozygous mutant. To test this hypothesis, beginning at embryonic day 12, Cntnap2+/- heterozygous mice were subjected to seven days of prenatal stress and subsequently examined for adult behaviors. Unlike wild-type littermates, prenatally stressed female Cntnap2+/- heterozygous mice exhibited social deficits. In addition, genomic profiling revealed disruptions in 5hmC throughout the striatal genome, which were similar to those seen in Cntnap2-/- homozygous mice. Finally, integration of the above data with striatal gene expression data revealed that differential hydroxymethylation correlated with altered transcript levels of genes shown to contribute to the deficits in GABAergic signaling and social behavior of the Cntnap2-/- homozygous mutant mouse (e.g., GABA receptors and Oxytocin). Thus, these data demonstrate that gene by environment interactions lead to deficits in social interactions and suggest that 5hmC levels likely contribute to this outcome. Here, the proposed studies will: 1) identify the functional role of 5hmC in social deficits resulting from prenatal stress; and 2) identify the contribution of oxytocin in social deficits exhibited following prenatal stress. These findings will identify stress-related molecular targets in the brain that are influenced by environmentally sensitive epigenetic mechanisms and may be involved in the etiology of developmental brain disorders. Importantly, the plan builds on the applicant's training in genomic studies, combining genomics will in-depth training in molecular and behavioral approaches.

项目摘要/摘要