The Role of Chromosome Y in Human Microglia and Neurodevelopment

Y 染色体在人类小胶质细胞和神经发育中的作用

• 批准号: 10680304
• 负责人: Celina Tien Nguyen
• 金额: $ 4.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680304
• 关键词: ATAC-seq; Affect; Age; Aneuploidy; Architecture; Area; Behavior assessment; Behavioral; Biological; Biological Models; Biology; Brain; Cells; ChIP-seq; Child; Chromosomes; Clinical; Data; Defect; Development; Diagnosis; Disease; Dose; Engraftment; Environment; Epigenetic Process; Female; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetic study; Genome; Genomics; Glass; Goals; Gonadal Steroid Hormones; Heritability; Human; Hypertrophy; Immune; Immunohistochemistry; Immunologics; In Vitro; Incidence; Inflammatory Response; Intervention; Knowledge; Laboratories; Lifestyle-related condition; Link; Macrophage; Measures; Mentorship; Microglia; Modeling; Molecular; Morphology; Mus; Neurodevelopmental Disorder; Outcome; Pathogenesis; Pathologic; Pathology; Phenotype; Physicians; Population Density; Prevalence; Production; Puberty; Regulation; Research; Resources; Rest; Risk Factors; Role; Scientist; Severities; Sex Bias; Sex Chromosomes; Sex Differences; Structure; Synaptosomes; Testing; Thick; Tissues; United States; Vertebral column; X Chromosome; Xenograft Model; Xenograft procedure; Y Chromosome; autism spectrum disorder; behavior test; boys; brain abnormalities; brain cell; career; cell type; cytokine; density; epidemiologic data; experience; gene network; genome-wide; genotypic sex; girls; glial activation; hands-on learning; human model; improved outcome; in vivo; individuals with autism spectrum disorder; induced pluripotent stem cell; innovation; insight; large datasets; male; migration; nerve stem cell; neurodevelopment; neuroimmunology; neuronal circuitry; neuropathology; novel; reproductive tract; sex; sexual dimorphism; skills; stem cell model; transcriptome sequencing; transcriptomics

PROJECT SUMMARY Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders, diagnosed in one in 44 children in the United States. Sex is among the most significant risk factors for ASD, with males being three to five times more likely than females to manifest the disorder. While epidemiological data documenting these sex differences in autism are abundant, there is currently little understanding of the fundamental differences between male and female biology that contribute to the sex biases in autism prevalence, severity, and clinical presentation. Based on mounting evidence implicating i) important microglial contributions to neurodevelopment, ii) sex-biased microglial activation in individuals with ASD, and iii) our preliminary findings regarding microglia- specific sex-linked gene expression, this proposal is built around the central hypothesis that genetic sex differences in microglia contribute the male bias in ASD. Sex chromosomes may be especially important drivers of sexual dimorphism in human brain development. For one, ASD manifests at an early age, before the puberty-associated increase in sex hormone production. Further, progressive chromosome Y aneuploidy (e.g. XY, XYY, XYYY, XYYY) leads to incrementally increased incidence of ASD. These observations suggest a significant role for chromosome Y for presenting ASD-related behaviors. Yet, there is a gap in knowledge about Y-linked genes and their contribution to sex dimorphism outside the reproductive tract and to ASD pathophysiology. Therefore, the project goal is to test the hypothesis that increasing chromosome Y dose in human microglia in vitro (Aim 1) and in a xenotransplantation model (Aim 3) results in microglial pathology, neuropathological defects, and ASD-associated behavioral deficits. Delineating genome wide transcriptional disruption and genome wide reorganization (Aim 2) will further uncover how chromosome Y-linked genes contribute to microglia-specific gene networks and expand our knowledge on Y- linked genes associated with ASD. The long-term goal is to generate a framework for studying genetic sex differences in microglia and their contributions to sex-biased brain development. A deeper understanding of the contribution and molecular regulation of microglia in ASD will lay the groundwork to ultimately identify novel potential sex-specific interventions to improve the outcomes for individuals with ASD. The proposed research will take place in the Coufal and Glass laboratories at UC San Diego. The Coufal lab expertise is in human induced pluripotent stem cell models of neuroimmunology, and the Glass lab has expertise in tissue-resident macrophage gene regulation and epigenetics. Through graduate coursework, mentorship, and hands-on learning, Celina will gain experience in stem cell modeling systems for human brain cell types and for approaching large datasets from a quantitative perspective. These skills will be valuable for the completion of the proposed research and for Celina’s future career as a physician-scientist.

项目摘要 自闭症谱系障碍（ASD）是最常见的神经发育障碍之一，被诊断为一个 在美国的44名儿童中。性是ASD最重要的危险因素之一，男性是三个 表现出这种疾病的可能性是女性的五倍。而流行病学数据文档这些 自闭症的性别差异丰富，目前对根本差异几乎没有理解 在男性和女性生物学之间导致自闭症患病率，严重性和临床的性行为偏见 推介会。基于安装证据，隐式i）对神经发育的重要小胶质贡献， ii）ASD患者的性偏见的小胶质细胞激活，以及iii）我们有关小胶质细胞的初步发现 特定的性别连接基因表达，该提案围绕遗传性别的中心假设构建 小胶质细胞的差异会导致ASD的男性偏见。 性染色体可能是人脑发育中性二态性的尤其重要的驱动因素。为了 第一，在青春期相关性激素产生的增加之前，ASD在很小的时候就表现出来。更远， 进行性染色体Y非整倍性（例如XY，Xyy，Xyyy，Xyyy）导致发病率增加 ASD。这些观察结果表明，染色体y在提出与ASD相关的行为方面具有重要作用。 然而，知识的差距关于y连锁基因及其对性二态性的贡献 生殖道和ASD病理生理学。因此，项目目标是检验以下假设 在体外人类小胶质细胞中增加染色体剂量（AIM 1）和异种移植模型（AIM 3） 导致小胶质病理学，神经病理学缺陷和与ASD相关的行为缺陷。描绘 基因组广泛的转录破坏和基因组广泛的重组（AIM 2）将进一步揭示 染色体y连锁基因有助于小胶质细胞特异性基因网络，并扩展了我们对Y-的知识 与ASD相关的链接基因。长期目标是生成一个研究遗传性别的框架 小胶质细胞的差异及其对性偏见的大脑发育的贡献。对 ASD中小胶质细胞的贡献和分子调节将奠定基础，以最终确定新颖 潜在的性别特定干预措施，以改善ASD患者的结果。 拟议的研究将在圣地亚哥分校的Coufal和Glass Laboratories中进行。 Coufal实验室 专业知识是人类诱导的多能干细胞神经免疫学的干细胞模型，玻璃实验室具有专业知识 在组织居民巨噬细胞基因调节和表观遗传学中。通过研究生课程，指导和 动手学习，Celina将获得人类脑细胞类型的干细胞建模系统的经验 从定量的角度接近大型数据集。这些技能对于完成 拟议的研究以及Celina作为身体科学家的未来职业。