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

• 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
• 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

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，有68名儿童在美国被诊断出患有自闭症谱系障碍（ASD），但有 目前尚无基本疗法。此外，流行病学研究表明近五个 男孩比女孩多的男孩受ASD的影响，但是这种性二态性背后的机制不好 理解。众所周知，遗传因素和环境因素都参与ASD发病机理。的 环境因素，流行病学表明，孕产妇感染引起的产前注射是 与ASD的风险增加相关，但是该链接背后的机制仍然需要阐明。 我们的实验室一直在努力了解环境因素如何影响正常的大脑 通过关注小胶质细胞，居民在中枢神经系统中的免疫核管如何进行开发和功能， 控制大脑中的先天免疫反应。更具体地说，我们对性恐怖是否感兴趣 及其相应的核受体（雌激素受体和雄激素受体）可能能够 诱导小胶质细胞中基因表达和表观遗传调节的变化，可以恢复正常的中枢神经系统 功能并改善神经炎症性疾病，例如ASD。我们对该提议的中心假设是 先天免疫信号传导，例如胎儿小胶质细胞中的Toll样受体（TLR）介导的炎症 参与诱导的特异性，类似ASD的行为变化。此外，我们预测 胎儿小胶质细胞中的抗炎ERβ配体确定它们对产前感染的敏感性 在ASD中观察到的男性偏见。我们将使用产前鼠标模型检验这些假设 炎症引起的ASD。 该提案的主要目标是了解对TLR介导的产前的差异反应 炎症会影响长期的胎儿小胶质细胞转录和表观遗传调节，从而导致ASD样 行为。此外，我们将确定ERβ介导的转录和表观遗传的调节是否是否 调节可以恢复受产前注射影响的正常小胶质细胞功能，从而改善ASD- 像后代的行为一样。该提案的预期总体影响是它将扩大机械 通过澄清它们的状态，了解不同的母校和胎儿TLR介导的信号传导途径 与在ASD中观察到的特定行为变化相关。我们还将充分阐明ERS及其如何 配体有助于在ASD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类似ASD的行为。