Human Neural Precursors from CNS Developmental Disorders: Down Syndrome

描述（由申请人提供）：唐氏综合征（DS）是一种常见的发育障碍，由21号染色体重复引起。理解导致DS的主要神经学特征的发育机制，即MR、癫痫发作和早发性阿尔茨海默病（AD），将取决于DS发育中观察到的差异的表征，而不是正常大脑。各种小鼠模型已被用作实验范式来理解这种差异，但在解释这些研究时存在明显的局限性，特别是因为人类大脑的生物学与其他物种不同。此外，DS脑的许多神经病理学特征 即改变的增殖、细胞死亡和神经元发生提示神经干细胞（NSC）群体内的缺陷。因此，我们建议调查来自唐氏综合征脑的人神经干细胞的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子。我们假设人类DS NSC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有助于DS CNS表型的特定功能途径相关。我们提出了一个两部分的研究，涉及人类DS神经祖细胞，调查DS皮质发育的机制：具体目标1：使用验证技术的定量mRNA分析技术，我们将确定基因改变的mRNA表达谱的多个人类DS神经祖细胞系相比，年龄匹配的控制和使用网络分析，以确定相互作用的蛋白质和发育途径的DS重要。具体目标二：我们将测试先前目标中预测的功能变化是否在DS NSC和人或16三体小鼠组织中明显。通过定量mRNA分析相当均匀的人类DS神经前体细胞和DS神经前体细胞在体外的功能分析，我们希望获得额外的洞察这种常见疾病的机制，并提供潜在的场所，发现新的治疗靶点。唐氏综合症（DS）是人类最常见的发育障碍之一，由21号染色体上的基因异常复制引起。目前的提议旨在从DS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允许开发治疗干预措施。

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.