Maternal Immune Activation in a Genetic Mouse Model of ASD

ASD 遗传小鼠模型中的母体免疫激活

• 批准号: 9117628
• 负责人: Anna Dunaevsky
• 金额: $ 37.53万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117628
• 关键词: Affect; Anti-Inflammatory Agents; Anti-inflammatory; Behavior; Behavioral; Brain; Dendritic Spines; Development; Disease; Electrophysiology (science); Environmental Risk Factor; Epidemiologic Studies; Etiology; Exhibits; Exposure to; Gene Expression; Genes; Genetic; Genetic Risk; Health; Image Analysis; Immune; Immune System and Related Disorders; Impairment; Infection; Lead; Mediating; Molecular; Mus; Mutant Strains Mice; Mutation; Pathway interactions; Pregnancy; Proteins; Regulation; Rett Syndrome; Risk; Risk Factors; Synapses; Testing; Up-Regulation; Whole-Cell Recordings; autism spectrum disorder; behavioral impairment; brain pathway; disorder risk; genetic risk factor; immune activation; in vivo imaging; insight; mouse model; mutant; neurobehavioral; neuropathology; novel; offspring; postnatal; prenatal exposure; prevent; risk variant

 DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) is a diverse disorder that is likely to be caused by a combination of genetic alterations and environmental insult during early development. Studies demonstrate an association between maternal immune activation (MIA) during pregnancy and an increased risk for ASD. Recent development of mouse models for prenatal exposure to maternal immune activation (MIA) show that the challenged offspring demonstrate impaired behaviors relevant to ASD as well as exhibit altered levels of immune proteins. A significant gap exists in understanding how altered immune state interacts with ASD risk genes to result in impaired behaviors. Here we will test the hypothesis altered regulation of MHC1 proteins is a mechanism of convergence for MIA and ASD genetic risk factors. Specifically, we will examine how mutations in mecp2, a gene responsible for the Rett syndrome and also associated with non-Rett ASD cases, interact with MIA. We will, combine behavioral, molecular, electrophysiological and synaptic in vivo imaging analyses in relevant brain circuits to determine how altered Mecp2 levels and MIA converge to results in altered behavior and neuropathology.

 描述（由申请人提供）：自闭症谱系障碍（ASD）是一种多样的疾病，可能是由遗传改变和早期发育过程中的环境损伤引起的。研究表明，怀孕期间母体免疫激活（MIA）与ASD风险增加之间存在关联。最近开发的产前暴露于母体免疫激活（MIA）的小鼠模型显示，受到挑战的后代表现出与ASD相关的受损行为，以及表现出免疫蛋白水平的改变。在理解改变的免疫状态如何与ASD风险基因相互作用以导致行为受损方面存在重大差距。在这里，我们将测试的假设改变调节MHC1蛋白是一种机制的收敛MIA和ASD遗传风险因素。具体来说，我们将研究mecp2（一种负责Rett综合征的基因，也与非Rett ASD病例相关）的突变如何与MIA相互作用。我们将结合联合收割机在相关脑回路中的行为、分子、电生理和突触体内成像分析，以确定改变的Mecp 2水平和MIA如何会聚以导致改变的行为和神经病理学。