Effects of maternal immune activation on GABRB3-deficient neocortical progenitors

母体免疫激活对 GABRB3 缺陷的新皮质祖细胞的影响

基本信息

批准号：
9275259
负责人：
Hyang Mi Moon
金额：
$ 6.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9275259
关键词：
Adherens Junction Adverse effects Affect Angelman Syndrome Apical Autistic Disorder Bacteria Bacterial Infections Behavioral Brain Butyric Acids CXCL1 gene Candidate Disease Gene Cell Cycle Cell division Cell physiology Cells Cerebral Palsy Child Chloride Channels Copy Number Polymorphism Cytoskeleton Data Defect Development Diagnosis Disease Drug Targeting Environmental Risk Factor Exposure to Fetal Development Fetal Growth Fetus Follow-Up Studies GABA Receptor Genes Genetic Predisposition to Disease Genetic Transcription Genetic Variation Goals Homeostasis Human Immune Immune response Immune signaling Immune system Immunologic Surveillance Impairment Incidence Infection Inherited Injury Interleukin-6 Intervention Lead Lipopolysaccharides Live Birth Maternal Exposure Maternal-Fetal Exchange Mediating Mediator of activation protein Metabolism Mitotic spindle Molecular Molecular Abnormality Mothers Mutation Neuraxis Neurodevelopmental Disability Neurodevelopmental Disorder Neurological outcome Neurons Neurotransmitters Outcome Pathogenesis Pathologic Pattern Phenotype Placenta Play Prader-Willi Syndrome Predisposition Pregnancy Pregnancy Complications Prevention strategy Production Regulation Rett Syndrome Risk Role Schizophrenia Signal Pathway Signal Transduction Social Interaction Stereotyped Behavior System TNF gene Testing Therapeutic Tissues Transcriptional Regulation Twin Studies United States Wild Type Mouse autism spectrum disorder career chemokine cytokine disorder risk epidemiology study experimental study fetal gamma-Aminobutyric Acid gene environment interaction genetic linkage analysis immune activation insight migration mouse model neocortical nerve stem cell neuropsychiatric disorder neutralizing antibody novel novel diagnostics offspring postnatal prenatal prevent progenitor protein complex public health relevance receptor receptor function relating to nervous system repetitive behavior synaptic function

项目摘要

DESCRIPTION (provided by applicant): With diagnoses at 1 in 68 live births in the United States, autism spectrum disorders (ASD) have been considered one of the most increasing child neuropsychiatric diseases. ASD is a neurodevelopmental disability characterized by social interaction deficits and repetitive or stereotyped behaviors. Twin studies and linkage analysis confirm that genetic abnormalities and environmental susceptibilities contribute to ASD. Human epidemiological studies support that maternal exposure to environmental risks like prenatal infection significantly increases the risk for ASD in offspring. Abnormal maternal immune activation (MIA) during early pregnancy results in deleterious outcomes in the central nervous system (CNS) of the developing fetus. As a critical maternal-fetal interface, the placenta also plays a key role in immune surveillance as well as fetal growth, and placental injury is strongly associated with risks for neurodevelopmental disease. We have identified a placental vulnerability to lipopolysaccharide (LPS, a compound that mimics bacterial infections) that is modulated by GABA receptor type A (GABAAR). Intriguingly, various GABAAR subtypes are expressed not only in CNS but also in immune cells and other tissues, where GABA signaling is found to modulate immune response. The most common GABAAR anomaly found in ASD cases is a maternally inherited copy number variation (CNV) at 15q11-13 which is implicated in ASD, Angelman syndrome, Prader Willi syndrome. My studies focus on novel ASD-risk mechanisms involving gene-environment interaction between one of the GABAARs, GABRB3, and MIA in an ASD mouse model. I hypothesize that a maternally inherited partial loss of GABRB3 and MIA could exacerbate fetal pathological brain phenotypes. I will determine if GABRB3 and MIA generate synergistic adverse effects on neural progenitor cell (NPC) functions in early development. Previously, we demonstrated that prenatal LPS challenge causes cortical patterning alterations in offspring with a pronounced effect on the abundance of Satb2-expressing upper layer callosal neurons and neuronal layer formation during early neocortical development. Preliminary data suggest that partial loss of Gabrb3 function greatly increases placental damage following LPS exposure. A short-term goal is to determine if GABAAR function in mother or maternal immune cells underlies this effect. In the long-term, I will assess whether GABAARs are valid drug targets in a mouse model of ASD. Confirmation that alterations in maternal GABAARs increase risk of ASD phenotypes may also lead to novel diagnostics that can identify mothers at risk during pregnancy. From this proposed study, I expect to find the key candidate molecules working downstream of GABRB3-mediated genetic predisposition combined with MIA. Importantly, administration of antagonists or neutralizing antibodies against these key mediator molecules may restore normal function of the GABA-MIA axis, which may potentially provide critical insight into therapeutic strategies to reduce risk of ASD.

描述（由申请人提供）：在美国，自闭症谱系障碍 (ASD) 被认为是增加最多的儿童神经精神疾病之一，是一种以社交互动缺陷和重复性为特征的神经发育障碍。双胞胎研究和连锁分析证实，遗传异常和环境易感性会导致自闭症谱系障碍（ASD），人类流行病学研究表明，母亲接触产前感染等环境风险会显着增加患自闭症谱系障碍的风险。妊娠早期母体免疫激活 (MIA) 异常会对后代的中枢神经系统 (CNS) 产生有害影响，胎盘作为重要的母胎界面，在免疫监视中也发挥着关键作用。以及胎儿的生长，胎盘损伤与神经发育疾病的风险密切相关，我们已经发现胎盘对脂多糖（LPS，一种模拟细菌感染的化合物）的脆弱性，而脂多糖是由 GABA 受体调节的。有趣的是，各种 GABAAR 亚型不仅在中枢神经系统中表达，而且在免疫细胞和其他组织中表达，其中 GABA 信号传导可调节免疫反应，自闭症谱系障碍 (ASD) 病例中最常见的 GABAAR 异常是母系遗传的拷贝。 15q11-13 的数字变异（CNV）与 ASD、Angelman 综合征、Prader Willi 综合征有关。我的研究重点是涉及基因-环境的新型 ASD 风险机制。在 ASD 小鼠模型中，GABAAR、GABRB3 和 MIA 之间的相互作用我发现，母系遗传的 GABRB3 和 MIA 的部分缺失可能会加剧胎儿的病理性脑表型。我将确定 GABRB3 和 MIA 是否对神经祖细胞产生协同不利影响。此前，我们证明产前 LPS 挑战会导致后代皮质模式改变，并对 Satb2 表达的丰度产生显着影响。早期新皮质发育过程中上层胼胝体神经元和神经元层的形成表明，Gabrb3 功能的部分丧失会大大增加 LPS 暴露后的胎盘损伤，短期目标是确定母体免疫细胞中的 GABAAR 功能是否是这种效应的基础。从长远来看，我将评估 GABAAR 是否是 ASD 小鼠模型中的有效药物靶标，确认母体 GABAAR 的改变会增加 ASD 表型的风险，也可能会导致新的结果。从这项拟议的研究中，我希望找到与 MIA 相结合的 GABRB3 介导的遗传易感性下游的关键候选分子。重要的是，针对这些关键介质分子的拮抗剂或中和抗体的施用可能会恢复。 GABA-MIA 轴的正常功能，这可能为降低 ASD 风险的治疗策略提供重要的见解。