The Role of Chromosome Y in Human Microglia and Neurodevelopment

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，在一个 在美国的44名儿童中。性别是ASD最重要的风险因素之一，男性是三个 比女性多五倍的可能性表现出这种疾病。虽然流行病学数据记录了这些 自闭症的性别差异是丰富的，目前对根本差异的了解很少 男性和女性生物学之间的差异，导致自闭症患病率，严重程度和临床 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个体中性别偏向的小胶质细胞激活，以及iii）我们关于小胶质细胞的初步发现- 特定的性连锁基因表达，这一建议是建立在中心假设，遗传性别 小胶质细胞的差异导致ASD中的男性偏好。 性染色体可能是人类大脑发育中性别二态性的特别重要的驱动因素。为 第一，ASD在青春期相关的性激素产生增加之前的早期就表现出来。此外，本发明还 进行性Y染色体非整倍体（如XY、XYY、XYYY、XYYY）导致发生率递增 的ASD。这些观察结果表明Y染色体在呈现ASD相关行为方面具有重要作用。 然而，关于Y连锁基因及其对性别二型性的贡献， 生殖道和ASD病理生理学。因此，该项目的目标是检验假设， 增加体外人小胶质细胞（目标1）和异种移植模型（目标3）中的Y染色体剂量 导致小胶质细胞病理学、神经病理学缺陷和ASD相关的行为缺陷。划定 全基因组转录破坏和全基因组重组（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，并扩大了我们对Y染色体的认识。 与ASD相关的基因长期目标是建立一个研究性别遗传的框架 小胶质细胞的差异及其对性别偏见的大脑发育的贡献。深入了解 小胶质细胞在ASD中的作用和分子调控将为最终确定新的 潜在的性别特异性干预措施，以改善ASD患者的结局。 这项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 专长是神经免疫学的人类诱导多能干细胞模型，Glass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。通过研究生课程，指导， 实践学习，塞利纳将获得经验，在干细胞建模系统的人类脑细胞类型和 从定量的角度来处理大型数据集。这些技能将是宝贵的完成 提议的研究和塞利纳未来的职业生涯作为一个物理学家，科学家。

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.