Establishing a human cellular model of sex differences in the brain

建立大脑性别差异的人类细胞模型

• 批准号: 9904767
• 负责人: Tracy L YOUNG-PEARSE
• 金额: $ 22.38万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904767
• 关键词: Adult; Affect; Age of Onset; Aggressive behavior; Alzheimer' s Disease; Animal Model; Animals; Antidepressive Agents; Antipsychotic Agents; Anxiety; Anxiety Disorders; Astrocytes; Autopsy; Behavioral Paradigm; Biological; Biological Assay; Biological Models; Biology; Bipolar Depression; Bipolar Disorder; Brain; Cell Line; Cell model; Cells; Cellular biology; Complement; Complex; Coupled; Development; Disease; ES Cell Line; Epigenetic Process; Estrogens; Exposure to; Female; Fibroblasts; Foundations; Fright; Future; Gene Expression; Gene Proteins; Genes; Genetic; Genome; Gonadal Hormones; Hand; Hippocampus (Brain); Hormonal; Hormones; Human; Human Engineering; Hypothalamic structure; Image; In Situ; Incidence; Individual; Investigation; Learning; Link; Literature; Long-Term Potentiation; Major Depressive Disorder; Maps; Medical; Memory; Mental disorders; Microglia; Modeling; Molecular; Morphology; Multiple Sclerosis; Nervous system structure; Neuraxis; Neuroglia; Neurologic; Neurons; Neurosciences; Outcome; Parkinson Disease; Pathway interactions; Patients; Pharmacotherapy; Play; Ploidies; Plug-in; Process; Property; Prosencephalon; Proteins; Proteomics; RNA; Regulation; Reproduction; Research Personnel; Resources; Risk; Role; Schizophrenia; Severities; Sex Bias; Sex Chromosomes; Sex Differences; Sexuality; Signal Transduction Pathway; Social Environment; Study models; Synapses; System; Testosterone; Tissues; Variant; Vertebral column; Woman; Work; X Chromosome; Y Chromosome; autism spectrum disorder; base; biological sex; brain cell; cell type; chromosome Y loss; density; differential expression; epidemiology study; genotypic sex; human male; human model; human stem cells; induced pluripotent stem cell; male; men; nervous system disorder; neural network; neurogenesis; neuroinflammation; neuropsychiatric disorder; response; sex; sexual dimorphism; stem cell model; stem cells; transcriptome sequencing; virtual

It is well established that biological sex affects risk, age-of-onset, and/or severity of many psychiatric and neurological diseases. Men have a higher incidence of Parkinson's disease, autism, and schizophrenia while women show a higher incidence of major depressive disorder, anxiety disorder, Alzheimer's disease and multiple sclerosis. Additionally, researchers have observed sex differences across nervous system properties related to neurogenesis, morphology, gene expression, synapse density, and connectivity. These differences could be due to differential genetics (XX vs XY), hormonal influence, and/or the complex effects of social environment. To understand the specific factors influencing both disease and “normal” brain function, it is critical to understand the cell and molecular bases of this variation between individuals. In spite of some compelling animal model work, studies analyzing the cell and molecular bases of sex differences in the human brain have, until very recently, been rare. Part of the reason for this is the lack of a human cellular model system for neuroscience that is both biologically relevant and genetically controlled. Here, we propose to establish a well controlled, defined, and manipulatable human stem cell model for studying the impact of genetic sex on cellular mechanisms underlying neuropsychiatric diseases. The system proposed would provide us and others a facile “plug-in” system for adding a sex differences component to stem cell-based analyses. In Aim 1, we propose to develop XX and XY stem cell lines that are fully isogenic outside of the sex chromosome complement. Sex differences cannot be definitively attributed to genetics as long as the autosomal genome also is also divergent, and since there is no natural occurrence of an autosomally isogenic male/female pair, we propose here to engineer human stem cell lines that are genetically identical with the exception of the sex chromosome complement. We will use a Klinefelter embryonic stem cell line (XXY) that we have in hand and develop new iPSCs from Klinefelter fibroblasts. We then will induce these lines to lose either a single X or Y chromosome, creating subclones of autosomally male and female stem cell lines. In Aim 2, we will use the autosomally isogenic stem cell system developed in SA1 to identify genes and proteins that are differentially affected by genetic sex. For this aim we will differentiate our isogenic XX and XY stem cells individually into neurons of the hypothalamus and of the cortex, astrocytes, and microglia and assay differential effects between XY and XX cells on gene and protein regulation.

众所周知，生物性别会影响许多精神疾病的风险、发病年龄和/或严重程度 和神经系统疾病。帕金森病、自闭症和精神分裂症的发病率较高。 而女性患重度抑郁症、焦虑症、阿尔茨海默病和 此外，研究人员还观察到神经系统特性的性别差异。 与神经发生、形态、基因表达、突触密度和连接性相关。 可能是由于差异遗传学（XX vs XY）、荷尔蒙影响和/或社会的复杂影响 要了解影响疾病和“正常”大脑功能的具体因素，需要了解环境。 尽管存在一些差异，但了解个体之间这种差异的细胞和分子基础至关重要。 引人注目的动物模型工作，分析人类性别差异的细胞和分子基础的研究 直到最近，大脑还很罕见，部分原因是缺乏人类细胞模型。 在这里，我们提出了既具有生物学相关性又具有遗传控制性的神经科学系统。 建立一个良好控制、明确且可操作的人类干细胞模型，用于研究 该系统将提供遗传性对神经精神疾病细胞机制的影响。 我们和其他人开发了一个简单的“插件”系统，用于在基于干细胞的分析中添加性别差异成分。 目标 1，我们建议开发性染色体外完全同基因的 XX 和 XY 干细胞系 只要常染色体基因组互补，性别差异就不能明确归因于遗传学 也是有分歧的，并且由于常染色体同基因男性/女性对不存在自然发生， 我们在此建议设计除性别外基因相同的人类干细胞系 我们将使用我们现有的 Klinefelter 胚胎干细胞系 (XXY) 和 从 Klinefelter 成纤维细胞中开发新的 iPSC，然后我们将诱导这些细胞系失去单个 X 或 Y。 染色体，创建常染色体男性和女性干细胞系的亚克隆 在目标 2 中，我们将使用 SA1 中开发的常染色体同基因干细胞系统，用于识别差异基因和蛋白质 为了这个目的，我们将同基因 XX 和 XY 干细胞分别分化为 下丘脑和皮质、星形胶质细胞和小胶质细胞的神经元并测定差异效应 XY 和 XX 细胞之间对基因和蛋白质调控的影响。