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，生物学会影响许多精神病的风险，发病年龄和/或严重性 和神经疾病。男性发生了更高的帕金森氏病，自闭症和精神分裂症的事件 妇女表现出更高的重度抑郁症，焦虑症，阿尔茨海默氏病和 多发性硬化症。此外，研究人员已经观察到神经系统特性之间的性别差异 与神经发生，形态，​​基因表达，突触密度和连通性有关。这些差异 可能是由于差异遗传学（XX与XY），激素影响和/或社会的复杂作用 环境。要了解特定因素都会影响疾病和“正常”大脑功能，这是 了解个人之间这种变化的细胞和分子碱基至关重要。尽管有一些 诱人的动物模型工作，分析人类性别差异的细胞和分子碱基的研究 直到最近，大脑一直很少见。原因的部分原因是缺乏人类细胞模型 神经科学系统既有生物学相关又受遗传控制。在这里，我们建议 建立一个良好控制，定义和可操作的人类干细胞模型，以研究的影响 遗传性别在神经精神疾病基础的细胞机制上。提议的系统将提供 我们和其他人一种可轻松的“插件”系统，用于在基于干细胞的分析中添加性别差异成分。在 AIM 1，我们建议开发XX和XY干细胞系在性染色体之外完全同生的干细胞系 补充。只要常染色体基因组，性别差异就不能明确地归因于遗传学 也有不同 我们在这里提议设计在遗传上相同的人类干细胞系，除了性别外 染色体完成。我们将使用我们手中有的KlineFelter胚胎干细胞系（XXY） 从KlineFelter成纤维细胞开发新的IPSC。然后，我们将诱导这些线丢失单个X或Y 染色体，形成雌雄同体和雌性干细胞系的子克隆。在AIM 2中，我们将使用 SA1中开发的自粘性等源性干细胞系统，以鉴定差异化的基因和蛋白质 受遗传性别的影响。为此，我们将分别区分我们的等源XX和XY干细胞 下丘脑和皮质，星形胶质细胞和小胶质细胞和测定差异作用的神经元 在基因和蛋白质调节的XY和XX细胞之间。