Microglial contribution to Down Syndrome Neuropathology

小胶质细胞对唐氏综合症神经病理学的贡献

• 批准号: 10566660
• 负责人: Nicole Gabriele Coufal
• 金额: $ 46.58万
• 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: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566660
• 关键词: 3-Dimensional; ATAC-seq; Adolescent; Affect; Architecture; Behavior assessment; Behavioral; Biogenesis; Brain; Cell Respiration; Cerebrum; ChIP-seq; Child; Chromosome 21; Chromosomes; Coculture Techniques; Cognition; Cognitive deficits; Complex; Data; Defect; Dendritic Spines; Development; Down Syndrome; Drug Screening; Engraftment; Environment; Epigenetic Process; Exhibits; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Goals; Heterogeneity; Human; Hypertrophy; Immune System Diseases; Immunologics; Impaired cognition; In Vitro; Individual; Inflammatory; Intellectual functioning disability; Interferons; Knowledge; Learning; Life; Longevity; Maps; Measurement; Memory; Mental disorders; Methodology; Methods; Microglia; Mission; Mitochondria; Modeling; Molecular; Morphology; Mus; Neurodegenerative Disorders; Neurodevelopmental Deficit; Neurons; Nitrogen; Organoids; Orthologous Gene; Outcome; Oxygen; Pathogenesis; Pathologic; Pathology; Patients; Peripheral; Phagocytosis; Phenotype; Regulation; Short-Term Memory; Stimulus; Synaptosomes; System; Testing; Therapeutic; Thick; Trisomy; United States; United States National Institutes of Health; Vertebral column; Xenograft Model; amyloid pathology; astrogliosis; behavior test; behavioral phenotyping; brain cell; cell type; clinical predictors; cognitive testing; comparison control; cytokine; density; disability; genome-wide; human model; human stem cells; improved outcome; in vivo; induced pluripotent stem cell; innovation; migration; mouse model; nerve stem cell; neurodevelopment; neuroimmunology; neuropathology; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; response; screening; single-cell RNA sequencing; stem cells; therapeutic target; transcriptome sequencing; transcriptomics; translational impact; translational model; vocalization; young adult

Summary/Abstract Down Syndrome (DS) affects over 200,000 individuals in the United States and is the most common genetic cause of intellectual and developmental disabilities in children and young adults. Down Syndrome arises from an extra third copy of chromosome 21, encompassing over 200 genes, which leads to genome wide transcriptional disruption. The brain cell-type specific contribution to DS neurodevelopmental deficits and the interaction between cognitive and immune dysfunction in DS are poorly understood. DS has been difficult to model due to limitations in murine orthologs and inadequacies of in vitro systems in modeling complex cellular interactions. Microglial pathology has been identified in individuals with DS, but the extent to which microglial dystrophy contributes to neurodevelopmental deficits is unknown. There is increasing evidence for the impact of microglia on brain development and microglia have been suggested as a novel therapeutic target in DS. This proposal is built around the central hypothesis that trisomy 21 causes microglial dysfunction and thereby contributes to the pathogenesis of intellectual and developmental disability in DS. Motivated by our strong preliminary data that in vitro microglia exhibit altered gene expression and functional phenotypes in neurodegenerative diseases and psychiatric disorders, we developed novel organoid microglia cocultures and a chimeric human microglia mouse model, whereby 80% of microglia are human in origin. Here we apply innovative in vitro and in vivo methods to ascertain the contribution of human DS microglia in neurodevelopment, neuronal function, and cognition. The project goal is to test the hypothesis that isolated trisomy 21 in human microglia and microglia-cerebral organoid cocultures in vitro (Aim 1) and in a xenotransplantation model of human microglia in vivo (Aim 2) results in microglial pathology, neuropathological defects, and behavioral deficits. Delineating genome wide transcriptional disruption and genome wide reorganization will uncover DS associated transcriptional dysregulation and expand our knowledge of DS associated genes. The long-term goal is to generate and validate in vitro and in vivo DS microglial models that can be employed for drug screening and to generate preclinical data. A deeper understanding of the contribution and molecular regulation of microglia in DS will lay the groundwork to ultimately identify novel potential therapeutic targets to improve the outcomes for individuals with DS.

总结/摘要 唐氏综合症（DS）影响了美国20多万人，是最常见的遗传病。 儿童和青少年智力和发育障碍的原因。唐氏综合症是由 21号染色体的额外第三个拷贝，包含200多个基因，这导致了全基因组的 转录破坏脑细胞类型特异性对DS神经发育缺陷的贡献以及 DS中认知和免疫功能障碍之间相互作用知之甚少。DS很难 由于小鼠直系同源物的局限性和体外系统在模拟复杂细胞中的不足， 交互.在DS患者中已经发现了小胶质细胞病理学，但小胶质细胞病理学改变的程度 营养不良导致神经发育缺陷的原因尚不清楚。越来越多的证据表明， 小胶质细胞在脑发育中的作用以及小胶质细胞已被认为是DS的新的治疗靶点。这 一项提案是围绕21三体导致小胶质细胞功能障碍，从而 有助于DS中智力和发育障碍的发病机制。在我们强大的 初步数据表明，在体外小胶质细胞表现出改变的基因表达和功能表型， 神经退行性疾病和精神疾病，我们开发了新的类器官小胶质细胞共培养物， 嵌合人小胶质细胞小鼠模型，其中80%的小胶质细胞来源于人。在这里我们申请 创新的体外和体内方法来确定人DS小胶质细胞在神经发育中的作用， 神经元功能和认知。该项目的目标是验证假设，孤立的21三体在人类 体外小胶质细胞和小胶质细胞-脑类器官共培养物（Aim 1）和 体内人小胶质细胞（目的2）导致小胶质细胞病理学、神经病理学缺陷和行为学改变。 赤字描述全基因组转录破坏和全基因组重组将揭示DS 相关的转录失调和扩大我们的知识DS相关基因。长期 目的是建立和验证可用于药物筛选的体外和体内DS小胶质细胞模型 并生成临床前数据。更深入地了解小胶质细胞的贡献和分子调控 将为最终确定新的潜在治疗靶点以改善结局奠定基础 对于DS患者。