The Role of Chromosome Y in Human Microglia and Neurodevelopment

项目总结 自闭症谱系障碍(Asd)是最常见的神经发育障碍之一，诊断为 在美国的44名儿童中。性别是自闭症的最重要的风险因素之一，男性是三个 出现这种疾病的可能性是女性的五倍。虽然流行病学数据记录了这些 自闭症的性别差异很大，目前对这些根本差异的了解很少 在自闭症患病率、严重程度和临床上导致性别偏见的男性和女性生物学之间的差异 演示文稿。基于越来越多的证据表明i)小胶质细胞对神经发育的重要贡献， Ii)ASD患者中性别偏见的小胶质细胞激活，以及iii)我们关于小胶质细胞的初步发现- 特定的与性别相关的基因表达，这一建议建立在基因性别的中心假设之上 小胶质细胞的差异导致了ASD的男性偏见。 性染色体可能是人类大脑发育中性二型性的特别重要的驱动因素。为 首先，自闭症在青春期相关的性激素分泌增加之前很早就表现出来。此外， 进行性Y染色体非整倍体(如XY、XYY、XYYY、XYYY)导致发病率递增 自闭症患者。这些观察结果表明，Y染色体在ASD相关行为中起着重要作用。 然而，人们对Y连锁基因及其对性别二型性的贡献的认识存在差距。 生殖道和ASD的病理生理学。因此，该项目的目标是测试假设 在体外和异种移植模型中增加人小胶质细胞的Y染色体剂量(AIM 1)和异种移植模型(AIM 3) 结果导致小胶质细胞病理、神经病理缺陷和ASD相关行为缺陷。划定 全基因组转录中断和全基因组重组(目标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，并扩大了我们对Y-Y的认识 与ASD相关的连锁基因。其长期目标是建立一个研究遗传性的框架 小胶质细胞的差异及其对性别偏见大脑发育的贡献。更深入地了解 小胶质细胞在ASD中的作用和分子调控将为最终鉴定新的 潜在的针对性别的干预措施，以改善ASD患者的预后。 这项拟议的研究将在加州大学圣地亚哥分校的Coufal和Glass实验室进行。Coufal实验室 专业领域是神经免疫学的人类诱导多能干细胞模型，而格拉斯实验室拥有专业知识 在组织驻留巨噬细胞基因调控和表观遗传学方面。通过研究生课程，指导，和 亲身实践学习，Celina将获得人类脑细胞类型的干细胞建模系统和 从量化的角度处理大型数据集。这些技能将对完成以下任务很有价值 这项拟议的研究和西琳娜未来作为内科科学家的职业生涯。

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.