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

基本信息

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
项目类别：
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

项目摘要

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.

摘要/摘要唐氏综合症（DS）在美国影响超过200,000人，是最常见的遗传儿童和年轻人的智力和发育障碍原因。唐氏综合症来自 21染色体的额外的第三份副本，包括200多个基因，这导致基因组宽转录中断。脑细胞类型对DS神经发育缺陷和 DS中认知和免疫功能障碍之间的相互作用知之甚少。 DS很难模型由于鼠直系同源物的局限性和体外系统不足的限制在建模复杂细胞中互动。在患有DS的个体中已经鉴定出小胶质细胞病理，但小胶质细胞的程度营养不良导致神经发育缺陷尚不清楚。有越来越多的证据证明关于脑发育和小胶质细胞的小胶质细胞已被认为是DS中的一种新型治疗靶标。这提案是围绕中心假设建立的，即三体第21章引起小胶质功能障碍，从而引起小胶质功能障碍 DS中智力和发育障碍的发病机理有助于。由我们的强者激励体外小胶质细胞表现出改变基因表达和功能表型的初步数据神经退行性疾病和精神疾病，我们开发了新型的类器官小胶质细胞培养和一种嵌合的人类小胶质细胞模型，其中80％的小胶质细胞是人类的。我们在这里申请创新的体外和体内方法，以确定人DS小胶质细胞在神经发育中的贡献，神经元功能和认知。项目目标是检验以下假设：小胶质细胞和小胶质细胞类器官共培养在体外（AIM 1）以及在异种移植模型中人体小胶质细胞体内（AIM 2）导致小胶质细胞病理学，神经病理缺陷和行为缺陷。划定基因组广泛的转录破坏和基因组范围的重组将发现DS 相关的转录失调并扩展我们对DS相关基因的了解。长期目标是生成和验证可以用于药物筛查的体外和体内小胶质细胞模型并生成临床前数据。对小胶质细胞的贡献和分子调节有更深入的了解在DS中将为最终确定新的潜在治疗靶标的基础，以改善结果适用于DS的人。