Genomic and Epigenomic Mechanisms of Maternal E-Cigarette induced Abnormal Brain Development

母亲电子烟导致大脑发育异常的基因组和表观基因组机制

• 批准号: 10670578
• 负责人: Charles Wang
• 金额: $ 99.73万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670578
• 关键词: ATAC-seq; Adolescent; Adverse effects; Affect; Anxiety; Attention deficit hyperactivity disorder; Biological Assay; Brain; Brain Injuries; Brain region; Cell Nucleus; Cell Therapy; Cells; Central Nervous System; Chromatin; Chronic; Computer Analysis; Copy Number Polymorphism; Coupled; DNA; DNA Sequence Alteration; Data; Databases; Development; Electronic cigarette; Embryo; Equilibrium; Exposure to; Fetus; Gender; Genes; Genomics; Goals; Health; Hyperactivity; Investigation; Knowledge; Measures; Mental Depression; Mental disorders; Methods; Modeling; Molecular; Morphology; Mutation; National Human Genome Research Institute; Neurodevelopmental Disorder; Neurons; Nicotine; Pathogenesis; Predisposition; Pregnant Women; Public Health; Rattus; Regulation; Risk; Single Nucleotide Polymorphism; Specific qualifier value; Synapses; System; Techniques; Technology; Time; Whole-Cell Recordings; autism spectrum disorder; bioinformatics tool; bisulfite sequencing; brain abnormalities; cell type; cognitive performance; electronic cigarette use; epigenomics; excitatory neuron; genome sequencing; genome wide association study; inhibitory neuron; insight; maternal cigarette smoking; methylome; multiple omics; neonatal brain; neonatal brain development; nerve stem cell; nervous system development; neurobehavior; offspring; postnatal; prenatal; prenatal exposure; prenatal nicotine exposure; single cell sequencing; single nucleus RNA-sequencing; therapeutic target; transcriptome; transcriptome sequencing; transcriptomics; vaping; whole genome

PROJECT SUMMARY/ABSTRACT Maternal smoking is a well-recognized public health concern associated with increased neurodevelopmental disorders and other health risks in offspring. Substantial evidence indicates various adverse effects of maternal smoking or prenatal nicotine exposure on neonatal brain development, e.g., hyperactivity, reduced cognitive performance, increased anxiety and depression, and increased susceptibility to brain injury. Electronic cigarettes (e-cig) have become popular in pregnant women and young adolescents. Growing evidence suggests that maternal e-cig use affects brain development, resulting in abnormal cortical neuronal morphology and aberrant neuro-behaviors in offspring. Using a rat prenatal e-cig exposure model and single-nucleus sequencing, we recently found that prenatal e-cig exposure disrupted excitatory-inhibitory (E/I) balance, ratio of excitatory/ inhibitory neurons, in the neonatal brain. E/I balance is crucial for normal brain development and functions, and its disruption has been postulated to underlie the pathogenesis of many neurodevelopmental disorders, including autism spectrum disorders, ADHD, and other psychiatric disorders. However, the underlying genomic and epigenomic mechanisms are still not known. This investigation seeks to fill this knowledge gap. Our hypothesis is that prenatal e-cig exposure induces epigenomic reprogramming and genomic alterations in the developing brain, which cause an E/I imbalance and consequently an increased risk for neurodevelopmental disorders. Exploiting the prenatal e-cig exposure model we developed recently, we propose three specific aims. Aim 1 will determine the spatial-temporal effects of prenatal e-cig exposure on brain development and progression of E/I imbalance using spatial genomics and single-cell sequencing techniques. Aim 2 will determine the epigenomic mechanisms regulating the prenatal e-cig induced E/I imbalance. Aim 3 will investigate whether prenatal e-cig causes genomic alterations (i.e., SNVs and CNVs) that are involved in E/I imbalance. Many cutting-edge genomic and epigenomic technologies are exploited in our studies, including spatial genomics, single-nucleus RNA-seq and chromatin accessibility (snATAC-seq), and state-of-the-art bioinformatics tools. OUTCOMES: Our study will: 1) identify the brain regions that show the E/I imbalance caused by prenatal e-cig exposure; 2) identify the key genes, genomic changes and epigenomic regulations responsible for the prenatal e-cig induced E/I imbalance; 3) produce a large amount of unprecedented omics data on the rat brain prenatally exposed to e-cig. IMPACT: Using a well-established intrauterine e-cig exposure model coupled with cutting-edge genomics and epigenomics approaches, our proposed studies will elucidate the genomic and epigenomic mechanisms underlying maternal e-cig induced abnormal brain development, providing valuable new insights into the effects of e-cig on the early central nervous system development, which will help explore promising molecular and cellular therapeutic targets for treating e-cig vaping-induced brain damage.

项目摘要/摘要 孕产妇吸烟是与神经发育增加有关的公认公共健康问题 后代的疾病和其他健康风险。大量证据表明母亲的各种不利影响 在新生儿大脑发育中吸烟或产前尼古丁暴露，例如，多动症，认知能力降低 表现，焦虑和抑郁症的增加以及增加对脑损伤的敏感性。电子烟 （电子烟）在孕妇和年轻青少年中变得很受欢迎。越来越多的证据表明 母体电子烟的使用会影响大脑发育，导致皮质神经元形态异常和异常 后代的神经行为。使用大鼠产前电子烟暴露模型和单核测序，我们 最近发现，产前电子烟暴露破坏了兴奋性抑制（E/I）平衡，兴奋性/ 抑制性神经元，在新生儿大脑中。 E/I平衡对于正常的大脑发育和功能至关重要，并且 它的破坏已被假定是为了构成许多神经发育障碍的发病机理，包括 自闭症谱系障碍，多动症和其他精神病障碍。但是，潜在的基因组和 表观基因组机制仍然不清楚。这项调查旨在填补这一知识差距。我们的假设 是，产前电子烟暴露在发育中引起表观基因组重编程和基因组改变 大脑会导致E/I失衡，因此会增加神经发育障碍的风险。 利用我们最近开发的产前电子烟暴露模型，我们提出了三个特定目标。目标1意志 确定产前电子烟暴露对脑发育和E/I进展的时空影响 使用空间基因组学和单细胞测序技术的不平衡。 AIM 2将确定表观基因组 调节产前E-cig诱导的E/I不平衡的机制。 AIM 3将研究产前电子烟是否 引起与E/I不平衡有关的基因组改变（即SNV和CNV）。许多尖端 在我们的研究中利用了基因组和表观基因组技术，包括空间基因组学，单核 RNA-Seq和染色质可及性（SNATAC-SEQ）以及最先进的生物信息学工具。结果：我们的 研究将：1）确定显示出由产前电子烟暴露引起的E/I不平衡的大脑区域； 2）识别 负责产前E-cig诱导的E/I的关键基因，基因组变化和表观基因组法规 失衡； 3）在暴露于电子烟的大鼠脑上产生大量前所未有的OMIC数据。 影响：使用公认的宫内E-cig暴露模型，加上尖端的基因组学和 表观基因组学方法，我们提出的研究将阐明基因组和表观基因组机制 孕产妇电子烟引起的脑发育异常，为影响提供了宝贵的新见解 电子烟关于早期中枢神经系统发育，这将有助于探索有希望的分子和 细胞治疗靶标，用于治疗E-CIG蒸发引起的脑损伤。