Genotype and Phenotype of Brainstem Injury in Autism

自闭症脑干损伤的基因型和表型

• 批准号: 6804229
• 负责人: PATRICIA M RODIER
• 金额: $ 7.88万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804229
• 关键词: autism; behavioral genetics; brain injury; clinical research; cooperative study

DESCRIPTION (provided by applicant): 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, Mbius 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.

描述（由申请人提供）：自闭症是一种神经发育障碍，具有几种已知的环境和遗传危险因素。 来自解剖学研究，致变性研究和合并症的研究的融合证据表明，自闭症的一个原因是脑干的早期玛尔达开发。 去年已经发表了几种新候选基因的ASD敏感性基因的证据，所有这些都是参与脑干胚胎发育的基因。 在项目I（自闭症的动物模型和损伤​​机制）中，研究人员将研究动物模型的神经解剖学，并使用实时PCR和原位杂交量化暴露于Teratogens的胚胎中的基因表达。 他们建议扩展研究与自闭症相关的致毒剂作用机理，以研究组蛋白脱乙酰基化的作用。 研究人员将比较TET反应性细胞系中遗传敏感性因子的多态性的转录功效，并查找暴露于子宫内teratogens的遗传学研究小鼠中的基因 - 环境相互作用。 目的是了解致变性剂和遗传异常如何对后脑产生相似的影响。 项目II。歧视人类和动物自闭症的行为是对有望歧视自闭症与其他发育障碍的行为任务的研究。 目的是开发可以作为引起自闭症的发育异常标记的动物任务，以便可以对项目中开发的动物模型进行与人类疾病的平行性测试。 抑制回报和拒绝条件是本应用程序中正在研究的任务。 项目III，自闭症和行为相关疾病的基因型和表型，已经评估了四个患有发育障碍（自闭症，Asperger综合症，M Bius综合症和语言综合症）和具有典型发展的发育障碍群体中早期发育基因的早期发育基因的突变的行为症状，次要的身体异常，神经 /眼科缺陷以及早期发育基因的突变。 调查人员建议增加两个小组 - 自闭症和智力低下的儿童和智商匹配的对照。 目的是确定这些疾病的表型或基因型特征表明常见病因。 项目IV，三个与自闭症相关的致毒剂的人群中的基因环境相互作用，将检查六个可疑的遗传易感性因素在子宫内暴露于已知与自闭症相关的三种致毒剂的人：替代剂：替代剂：替代剂，瓣膜酸，瓣膜酸和米索罗多尔。 研究人员建议确定符合ASD诊断标准的这些人群的成员是否是具有遗传危险因素的成员。 该项目与动物中提出的基因环境研究密切相关。