Estrogen receptor (ER)β-mediated repression of prenatal inflammation in fetal microglia and its impact on autism

雌激素受体 (ER)β 介导的胎儿小胶质细胞产前炎症抑制及其对自闭症的影响

基本信息

批准号：
9338910
负责人：
Kaoru Saijo
金额：
$ 32.58万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
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：
2017-08-01 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9338910
关键词：
ATAC-seq Address Affect Androgen Receptor Anti-Inflammatory Agents Anti-inflammatory Autistic Disorder Bacterial Infections Behavior Behavioral Biological Assay Brain Cells Child Defect Development Diagnosis Disease Encephalitis Environmental Risk Factor Enzymes Epidemiology Epigenetic Process Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Exhibits Female Gene Expression Generations Genes Genetic Genetic Transcription Goals Gonadal Steroid Hormones Homeostasis Hormone Receptor Immune Immune signaling Infection Inflammation Innate Immune Response Lead Learning Disabilities Ligands Link Mediating Microglia Modeling Mus Neuraxis Neurodevelopmental Disorder Nuclear Hormone Receptors Nuclear Receptors Output Pathogenesis Pathology Patients Pattern recognition receptor Poly I-C Pregnancy Repression Risk Role Sentinel Signal Pathway Stimulus Testing Time Toll-like receptors Transcriptional Regulation Virus Diseases autism spectrum disorder behavior change boys cytokine differential expression epidemiology study epigenetic regulation fetal genome wide association study girls hormone metabolism improved in vivo innate immune function interest male mouse model neuroinflammation novel therapeutic intervention offspring pathogen prenatal prevent programs repetitive behavior response sexual dimorphism social learning synaptic function synaptic pruning transcription factor transcriptome sequencing

项目摘要

Abstract One in 68 children are diagnosed with autism spectrum disorders (ASD) in the US, yet there are currently no fundamental therapies available. Furthermore, epidemiological research suggests that nearly five times more boys than girls are affected by ASD, but the mechanisms behind this sex dimorphism are not well understood. It is known that both genetic and environmental factors are involved in ASD pathogenesis. Of the environmental factors, epidemiology suggests that prenatal inflammation induced by maternal infection is associated with an increased risk of ASD, yet the mechanisms behind this link still need to be elucidated. Our lab has been working on understanding how environmental factors affect normal brain development and functions by focusing on how microglia, resident immune cells in the central nervous system, control innate immune responses in the brain. More specifically, we are interested in whether sex hormones and their corresponding nuclear receptors (Estrogen Receptors and Androgen Receptor) may be able to induce changes in gene expression and epigenetic regulation in microglia that can restore normal CNS functions and improve neuroinflammatory diseases such as ASD. Our central hypothesis for this proposal is that innate immune signaling, such as toll-like receptor (TLR)-mediated inflammation in fetal microglia, is involved in inducing specific, ASD-like behavior changes. Furthermore, we predict that the expression levels of anti-inflammatory ERβ ligands in fetal microglia determine their sensitivity to prenatal inflammation and contribute to the male bias observed in ASD. We will test these hypotheses using mouse models of prenatal inflammation-induced ASD. The primary goal of this proposal is to understand how differential responses to TLR-mediated prenatal inflammation can affect long-term fetal microglial transcription and epigenetic regulation, resulting in ASD-like behaviors. Moreover, we will determine whether modulation of ERβ-mediated transcription and epigenetic regulation can restore normal microglial functions affected by prenatal inflammation, thus ameliorating ASD- like behaviors in offspring. The expected overall impact of this proposal is that it will expand the mechanistic understanding of distinct maternal and fetal TLR-mediated signaling pathways by clarifying how they are associated to specific behavior changes observed in ASD. We will also fully elucidate how ERs and their ligands contribute to the male bias observed in ASD and how these ligands can restore homeostasis in microglia to improve ASD-like behaviors in a mouse model.

抽象的在美国，每 68 名儿童中就有 1 名被诊断患有自闭症谱系障碍 (ASD)，但仍有目前尚无可用的基本治疗方法，此外，流行病学研究表明，近五种疾病。受自闭症谱系障碍影响的男孩是女孩的几倍，但这种性别二态性背后的机制尚不清楚据了解，遗传和环境因素都参与 ASD 的发病机制。环境因素，流行病学提示，母体感染诱发的产前炎症是与 ASD 风险增加有关，但这种联系背后的机制仍需阐明。我们的实验室一直致力于了解环境因素如何影响正常大脑通过关注中枢神经系统中的常驻免疫细胞小胶质细胞的发育和功能，更具体地说，我们感兴趣的是性激素是否控制大脑中的先天免疫反应。及其相应的核受体（雌激素受体和雄激素受体）可能能够诱导小胶质细胞基因表达和表观遗传调控的变化，从而恢复正常的中枢神经系统功能并改善神经炎症疾病，例如自闭症谱系障碍（ASD），我们对此提议的中心假设是先天免疫信号传导，例如胎儿小胶质细胞中 Toll 样受体 (TLR) 介导的炎症，参与诱导特定的、类似 ASD 的行为变化。此外，我们预测的表达水平。胎儿小胶质细胞中的抗炎 ERβ 配体决定其对产前炎症的敏感性我们将使用产前小鼠模型来测试这些假设。炎症诱发的 ASD。该提案的主要目标是了解对 TLR 介导的产前反应的差异如何炎症可长期影响胎儿小胶质细胞转录和表观遗传调控，导致 ASD 样症状此外，我们将确定是否调节 ERβ 介导的转录和表观遗传。调节可以恢复受产前炎症影响的正常小胶质细胞功能，从而改善 ASD- 该提案的预期总体影响是，它将扩大这一机制。通过阐明不同的母体和胎儿 TLR 介导的信号传导途径，了解它们的作用我们还将充分阐明 ER 及其如何与 ASD 中观察到的特定行为变化相关。配体有助于在自闭症谱系障碍中观察到的男性偏见，以及这些配体如何恢复体内平衡小胶质细胞改善小鼠模型中的 ASD 样行为。