GABRB3 and Placental Vulnerability in ASD

ASD 中的 GABRB3 和胎盘脆弱性

基本信息

批准号：
8619661
负责人：
Theo D Palmer
金额：
$ 58.25万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8619661
关键词：
Agonist Alleles Angelman Syndrome Attention Attenuated Autistic Disorder Behavioral Benign Blood Vessels Brain Cells Child Chromosome abnormality Chromosomes Cytogenetics Cytokine Signaling Data Defect Development Environmental Risk Factor Event Exploratory Behavior Fetus Future GABA-A Receptor Genes Genetic Genetic Models Genetic Predisposition to Disease Hemorrhage Hypoxia Immune Immune response Immune system Incidence Infection Inflammation Inheritance Patterns Intervention Lead Lipopolysaccharides Live Birth Modeling Mothers Mus Neurological outcome Neurons Pathology Patients Perfusion Peripheral Pervasive Development Disorder Phenotype Placenta Prader-Willi Syndrome Pregnancy Regulation Rett Syndrome Risk Risk Factors Role Socialization Testing Tissues Work autism spectrum disorder cytokine fetal fetus at risk gamma-Aminobutyric Acid gene environment interaction immune activation immune function loss of function novel offspring prenatal prevent public health relevance receptor research study response

项目摘要

DESCRIPTION (provided by applicant): The GABA(A) receptor ¿3 subunit gene GABRB3 has been strongly implicated in the pervasive developmental disorders (PDD). GABRB3 lies within chromosome 15q11-13, and anomalies in this region are associated with Rett syndrome, Prader-Willi syndrome, Angelman Syndrome, and are the single most frequent cytogenetic abnormality found in the autism spectrum disorders (ASD). It has recently been recognized that peripheral GABA(A) receptors are involved in immune cell regulation and that activation of GABA(A) receptors can attenuate tissue inflammation. Maternal inflammation during pregnancy has been an environmental factor associated with ASD and we have found that loss of one GABRB3 allele in mother and fetus is sufficient to markedly increase placental pathology in response to cytokines produced by a mild maternal innate immune response in mice. In contrast, activating GABA(A) receptors during a maternal immune event attenuates the impact to the fetus. This implicates GABA(A)-related immune alterations and placental vulnerability as a potential gene-environment interaction which is associated with increased risk of ASD and other PDDs. Importantly, the maternal inheritance pattern of 15q11-13 anomalies suggests that GABA(A)-related immune functions may be altered in mother, as well as in the placenta and fetus. The experiments proposed here test whether selective loss of GABARB3 in the mother, placenta or fetus increase the risk of developing autistic features in offspring following a prenatl maternal immune event.

描述（由应用程序提供）：GABA（a）接收器»3个亚基GABRB3与普遍的发育障碍（PDD）密切相关。 GABRB3位于15q11-13染色体内，该区域的异常与RETT综合征，Prader-Willi综合征，Angelman综合征有关，并且是自闭症谱系障碍（ASD）中最常见的细胞遗传学异常。最近已经认识到，外周GABA（A）受体参与免疫细胞调节，GABA的激活（A）受体可以减弱组织感染。怀孕期间的产妇炎症一直是与ASD相关的环境因素，我们发现，母亲和胎儿中一个GABRB3等位基因的损失足以显着增加舒张性病理学，以响应小鼠中轻度母体孕妇先天性免疫反应产生的细胞因子。相反，在母体免疫事件中激活GABA（A）受体会减轻对胎儿的影响。这意味着GABA（A）相关的免疫学改变和位置脆弱性，作为潜在的基因环境相互作用，与ASD和其他PDD的风险增加有关。重要的是，15q11-13异常的母体遗传模式表明，母亲以及胎盘和胎儿中可能会改变与GABA（A）相关的免疫学功能。此处提出的实验测试了母亲，胎盘或胎儿中Gabarb3的选择性损失是否会增加在PRENATL MERD MERF evers事件后后代发展加速特征的风险。