A Novel Approach to Molecular Cell Pathologies of Human Down Syndrome and DS-AD

摘要 唐氏综合征（DS），或21三体，是发育和认知障碍的主要遗传原因， 孩子随着DS患者的寿命延长，我们现在意识到大多数人会患上早发性阿尔茨海默病（AD）。 此外，患有DS的人患先天性心脏病、骨髓增生性疾病的风险大大增加。 和白血病，以及免疫和其他系统缺陷。因此，理解三个正常的拷贝 21号染色体上的基因影响细胞表达谱和细胞表型不仅对DS重要， 但是对于那些折磨非DS人群的疾病，特别是AD， 我们这个时代研究人员试图确定转录和表型变化，负责 DS的各个方面;然而，这项工作受到个体变异和遗传复杂性的阻碍 和DS的表型变异性。因此，迫切需要更好的方法来确定特定的细胞， 病理学和基因途径，这些方面的综合征，并促进筛选药物， 纠正他们。我们最近创建并演示了这样一个系统， 初步结果，建议使用它来“解剖”21三体对全基因组途径的细胞影响 和表型，在未分化的多能和神经DS干细胞。我们将利用这一独特的 系统来研究21三体对特异性表达的全基因组变化的最直接影响。 基因和途径（Aim 1），将其与特定的神经细胞表型变化（Aim 2）相关联，并最终 检查特异性Chr 21基因（目的3）对DS和AD病理学的贡献。而不是专注于一个或 更多的“青睐”方面或假设，我们提出了一个公正和广泛的方法，支持几个 他们是分子细胞生物学和神经生物学领域的领导者。这种新方法 有很大的希望克服挑战，混淆了明确的理解基础生物学的 DS，从而为治疗DS的长期转化努力提供基础。更好地了解 在人DS中被干扰的基因和细胞途径对于药物疗法的开发是重要的（对于DS和 AD），但也对“染色体沉默”或基因疗法的潜在发展有影响。 这项工作也对理解基因组平衡，协调水平， 基因在整个基因组中的表达。

ABSTRACT Down Syndrome (DS), or Trisomy 21, is the leading genetic cause of developmental and cognitive disability in children. As individuals with DS live longer, we now realize most develop early-onset Alzheimer Disease (AD). In addition, people with DS have greatly increased risk of congenital heart disease, myeloproliferative disorder and leukemia, as well as immune and other system defects. Hence, understanding how three copies of normal genes on chromosome 21 impacts cell expression profiles and cell phenotypes is important not only for DS, but for conditions that afflict the non-DS population, particularly AD, perhaps the biggest medical challenge of our time. Researchers have sought to identify the transcriptional and phenotypic changes responsible for the various aspects of DS; however, this work is hampered by individual variation as well as the genetic complexity and phenotypic variability of DS. Thus, there is a critical need for better ways to determine specific cellular pathologies and gene pathways which underlie aspects of the syndrome, and to facilitate screening of drugs to correct them. We have recently created and demonstrated such a system and, supported by compelling preliminary results, propose to use it to “dissect” the cellular impact of Trisomy 21, on genome-wide pathways and phenotypes, in undifferentiated pluripotent and in neural DS stem cells. We will capitalize upon this unique system to investigate the most direct effects of Trisomy 21 on genome-wide changes in expression of specific genes and pathways (Aim1), correlate this with specific neural cell phenotypic changes (Aim2), and ultimately examine the contribution of specific Chr21 genes (Aim 3) to DS and AD pathology. Rather than focus on one or more “favored” aspects or hypotheses, we propose an unbiased and broad approach, supported by several collaborators who are leaders in their areas of molecular cell biology and neurobiology. This novel approach has great promise to surmount challenges that have confounded clear understanding of the basic biology of DS, and thus provide the foundation for longer-term translational efforts to treat DS. Greater understanding of genes and cell pathways perturbed in human DS is important for development of drug therapies (for DS and AD), but also has implications for the potential development of “chromosome silencing” or gene therapies. This work also has broad basic impact for understanding genome balance, the coordinated levels of expression for genes throughout the genome.