Human Neural Precursors from CNS Developmental Disorders: Down Syndrome

中枢神经系统发育障碍的人类神经前体：唐氏综合症

• 批准号: 7470915
• 负责人: VOLNEY L SHEEN
• 金额: $ 21.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-04 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470915
• 关键词: ARNT2 gene; Adopted; Age; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Brain; Calcium-Binding Proteins; Cell Death; Cell Line; Characteristics; Chromosomes, Human, Pair 21; Congenital Abnormality; Congenital Heart Defects; Data; Defect; Development; Disease; Down Syndrome; Face; Financial compensation; Free Radicals; Gene Duplication; Gene Expression; Gene Expression Profile; Genes; Genome; Goals; HIF1A gene; Hearing problem; Human; Human Biology; Human Identifications; In Vitro; Individual; Infection; Injury; Lead; Mediating; Mental Retardation; Messenger RNA; Modeling; Molecular; Molecular Profiling; Network-based; Neurologic; Neurons; Pathway Analysis; Pathway interactions; Phenotype; Population; Process; Proteins; Public Health; Reactive Oxygen Species; Research; Sampling; Seizures; Techniques; Technology; Testing; Therapeutic Intervention; Tissues; Up-Regulation; Vision; aquaporin 4; brain tissue; cell type; developmental disease; human stem cells; insight; mRNA Expression; mouse Trisomy 16; mouse model; nerve stem cell; normal aging; novel therapeutics; progenitor; relating to nervous system; response; therapeutic target; water channel

DESCRIPTION (provided by applicant): Down syndrome (DS) is a common developmental disorder caused by a duplication of chromosome 21. Understanding the developmental mechanisms that lead to the primary neurological features of DS, namely MR, seizures, and premature Alzheimer's disease (AD), will depend upon characterization of the differences observed in the development of the DS, as opposed to normal brain. Various mouse models have been used as experimental paradigms to understand such differences, but clear limitations exist in the interpretation of these studies, particularly since the biology of human brains are different from those of other species. Moreover, many of the neuropathological features of DS brain namely altered proliferation, cell death, and neuronogenesis suggest a defect within the neural stem cell (NSC) population. Thus, we propose to investigate the mRNA profiles of human NSCs derived from Down syndrome brain and characterize the cellular and molecular factors which are disrupted in this vitro developmental model. We hypothesize that altered expression of genes on chromosome 21 in human DS NSCs will lead to identifiable mRNA expression changes throughout the genome, and that these changes can be associated with specific functional pathways that will contribute to the DS CNS phenotype. We propose a two-part study involving human DS neural progenitors, to investigate the mechanisms of DS cortical development: Specific Aim 1: Using validated techniques of quantitative mRNA profiling technology, we will identify genes altered on mRNA expression profiles of multiple human DS neural progenitor lines as compared to age-matched controls and use network analysis to identify interacting proteins and developmental pathways important for DS. Specific Aim 2: We will test whether the functional changes predicted in the prior aim are apparent in the DS NSCs and human or trisomy 16 mouse tissues. Through quantitative mRNA analyses of fairly uniform human DS neural progenitors and functional analyses of DS neural precursors in vitro, we hope to gain additional insight into mechanisms underlying this common disorder and provide potential venues for the discovery of new therapeutic targets. PUBLIC HEALTH RELEVANCE Down Syndrome (DS) is one of the most common developmental disorders in humans and is caused by the abnormal duplication of genes on chromosome 21. The current proposal seeks to generate and study human stem cells from DS brain. Understanding the genes which are disrupted in this disorder will allow for the development of therapeutic interventions.

描述（由申请人提供）：唐氏综合症（DS）是一种由21号染色体重复引起的常见发育障碍。了解导致退行性椎体滑移主要神经学特征（即MR、癫痫发作和早发性阿尔茨海默病（AD））的发育机制，将取决于对退行性椎体滑移与正常大脑发育中观察到的差异的描述。各种各样的小鼠模型已经被用作实验范例来理解这些差异，但在这些研究的解释中存在明显的局限性，特别是因为人类大脑的生物学与其他物种不同。此外，退行性痴呆脑的许多神经病理特征，即增殖改变、细胞死亡和神经发生，表明神经干细胞（NSC）群体存在缺陷。因此，我们建议研究来自唐氏综合征大脑的人类NSCs的mRNA谱，并表征在这种体外发育模型中被破坏的细胞和分子因素。我们假设人类DS NSCs中21号染色体上基因表达的改变将导致整个基因组中可识别的mRNA表达变化，并且这些变化可能与特定的功能途径相关，这些功能途径将有助于DS CNS表型。我们提出了一项涉及人类DS神经祖细胞的两部分研究，以研究DS皮质发育的机制：具体目标1：使用经过验证的定量mRNA分析技术，我们将识别与年龄匹配对照相比，多个人类DS神经祖细胞系mRNA表达谱上改变的基因，并使用网络分析来识别对DS重要的相互作用蛋白和发育途径。特异性目标2：我们将测试先前目标中预测的功能变化在DS NSCs和人类或16三体小鼠组织中是否明显。通过对相当统一的人类DS神经前体细胞的定量mRNA分析和体外DS神经前体细胞的功能分析，我们希望进一步了解这种常见疾病的机制，并为发现新的治疗靶点提供潜在的场所。唐氏综合症（DS）是人类最常见的发育障碍之一，由21号染色体上基因的异常重复引起。目前的提议是寻求从退行性痴呆大脑中产生和研究人类干细胞。了解在这种疾病中被破坏的基因将有助于开发治疗干预措施。