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: 7602965
• 负责人: VOLNEY L SHEEN
• 金额: $ 25.5万
• 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 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602965
• 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; Intervention Studies; Lead; Mediating; Mental Retardation; Messenger RNA; Modeling; Molecular; Molecular Profiling; Network-based; Neurologic; Neurons; Pathway Analysis; Pathway interactions; Phenotype; Process; Proteins; Reactive Oxygen Species; Sampling; Seizures; Techniques; Technology; Testing; Therapeutic Intervention; Tissues; Up-Regulation; Vision; aquaporin 4; brain tissue; cell type; developmental disease; genome-wide; human stem cells; insight; mRNA Expression; mouse Trisomy 16; mouse model; nerve stem cell; new therapeutic target; normal aging; premature; progenitor; public health relevance; response; stem cell population; 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）是由21染色体的重复引起的常见发育障碍。了解导致DS的主要神经功能特征的发育机制，即MR，癫痫发作和早产阿尔茨海默氏病（AD），将取决于与DS的差异相对的差异，而不是与DS相反。各种小鼠模型已被用作实验范式来理解这种差异，但是在解释这些研究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的生物不同。此外，DS脑的许多神经病理学特征都改变了增殖，细胞死亡和神经发生，这表明神经干细胞（NSC）群体中存在缺陷。因此，我们建议研究源自唐氏综合症大脑的人类NSC的mRNA谱，并表征该体外发育模型中破坏的细胞和分子因子。我们假设人类DS NSC中21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，并且这些变化可以与特定的功能途径相关联，这将有助于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：特定目的1：使用经过验证的定量mRNA分析技术的技术，我们将确定基因在多个人类DS神经祖细胞系的mRNA表达谱上改变了与年龄匹配的网络分析和使用互动蛋白相比，多种人类DS神经祖细胞系的基因和增长的良好依赖性依赖性的蛋白质和发展。具体目标2：我们将测试先前目标中预测的功能变化是否在DS NSC和人类或三体术16小鼠组织中显而易见。通过对人类DS神经祖细胞相当均匀的MRNA分析和体外DS神经前体的功能分析，我们希望能够获得对这种常见疾病的基础机制的更多见解，并为发现新的治疗靶标提供了潜在的场所。公共卫生相关性唐氏综合症（DS）是人类最常见的发育障碍之一，是由21染色体上基因的异常重复引起的。当前的建议旨在从DS脑中产生和研究人类干细胞。了解这种疾病中破坏的基因将允许发展治疗干预措施。

项目成果

Generation of neural stem cells from discarded human fetal cortical tissue.

• DOI: 10.3791/2681
• 发表时间: 2011-05-25
• 期刊: Journal of visualized experiments : JoVE
• 作者: Lu, Jie;Delli-Bovi, Laurent C;Sheen, Volney L
• 通讯作者: Sheen, Volney L

Lubricated biodegradable polymer networks for regulating nerve cell behavior and fabricating nerve conduits with a compositional gradient.

• DOI: 10.1021/bm201372u
• 发表时间: 2012-02-13
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Cai, Lei;Lu, Jie;Sheen, Volney;Wang, Shanfeng
• 通讯作者: Wang, Shanfeng

Seizure or syncope: lessons over time.

癫痫发作或晕厥：随着时间的推移吸取教训。

• DOI: 10.1016/j.jocn.2011.06.017
• 发表时间: 2012
• 期刊: Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia
• 作者: Sheen,VolneyL

S100B induces tau protein hyperphosphorylation via Dickopff-1 up-regulation and disrupts the Wnt pathway in human neural stem cells.

• DOI: 10.1111/j.1582-4934.2008.00159.x
• 发表时间: 2008-06
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Esposito G;Scuderi C;Lu J;Savani C;De Filippis D;Iuvone T;Steardo L Jr;Sheen V;Steardo L
• 通讯作者: Steardo L

Optimal poly(L-lysine) grafting density in hydrogels for promoting neural progenitor cell functions.

• DOI: 10.1021/bm300381d
• 发表时间: 2012-05-14
• 期刊: BIOMACROMOLECULES
• 影响因子: 6.2
• 作者: Cai, Lei;Lu, Jie;Sheen, Volney;Wang, Shanfeng
• 通讯作者: Wang, Shanfeng