Human Neural Precursors from CNS Developmental Disorders: Down Syndrome

描述(申请人提供)：唐氏综合症(DS)是一种常见的发育障碍，由21号染色体重复引起。了解导致DS的主要神经学特征的发育机制，即MR、癫痫和早产儿阿尔茨海默病(AD)，将取决于DS与正常大脑在发育过程中观察到的差异的特征。不同的小鼠模型被用作理解这种差异的实验范式，但这些研究的解释存在明显的局限性，特别是因为人类大脑的生物学与其他物种的不同。此外，DS脑的许多神经病理特征，即细胞增殖、细胞死亡和神经元发生的改变，表明神经干细胞(NSC)群体中存在缺陷。因此，我们建议研究从唐氏综合征脑来源的人神经干细胞的mRNA谱，并表征在这一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有关，这些途径将有助于DS CNS表型。我们提出了一项涉及人类DS神经前体细胞的两部分研究，以探讨DS皮质发育的机制：具体目标1：使用经过验证的定量mRNA图谱技术，我们将识别与年龄匹配的对照相比，多个人类DS神经前体细胞系的mRNA表达谱上的基因变化，并使用网络分析来确定相互作用的蛋白质和对DS重要的发育途径。具体目标2：我们将测试在先前目标中预测的功能变化是否在DS NSCs和人类或16三体小鼠组织中明显。通过对相当均匀的人DS神经前体细胞的定量mRNA分析和对DS神经前体细胞的体外功能分析，我们希望对这种常见疾病的发病机制有更深入的了解，并为发现新的治疗靶点提供潜在的场所。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，由21号染色体上基因的异常复制引起。目前的提议寻求从DS脑中产生和研究人类干细胞。了解这种疾病中被破坏的基因将有助于开发治疗干预措施。

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.