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

人类唐氏综合症和 DS-AD 分子细胞病理学的新方法

• 批准号: 10178060
• 负责人: JEANNE Bentley LAWRENCE
• 金额: $ 40.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-12 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178060
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Area; Biological Assay; Biology; CRISPR/Cas technology; Cell Differentiation process; Cell Lineage; Cell physiology; Cells; Cellular Morphology; Cellular Structures; Cellular biology; Child; Chromosome 21; Chromosomes; Cilia; Code; Coupled; Defect; Dendritic Spines; Detection; Development; Developmental Delay Disorders; Developmental Disabilities; Disease; Down Syndrome; Drug Screening; Equilibrium; Female; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Human; Human Pathology; Immune; In Vitro; Individual; Lead; Medical; Messenger RNA; Methods; MicroRNAs; Mitochondria; Molecular; Morphology; Myeloproliferative disease; Nerve Degeneration; Neural Crest; Neurobiology; Neurofibrillary Tangles; Neuroglia; Neurologic; Neuronal Differentiation; Neurons; Pathology; Pathway interactions; Patients; Pharmacotherapy; Phenotype; Population; Preclinical Testing; Presenile Alzheimer Dementia; Proteins; Publishing; RNA; RNA Interference; Regulation; Research; Research Personnel; Risk; Senile Plaques; Syndrome; System; Technology; Testing; Therapeutic; Time; Trisomy; Undifferentiated; Untranslated RNA; Variant; Work; X Chromosome; X Inactivation; base; beta-site APP cleaving enzyme 1; cell type; cellular pathology; cognitive disability; congenital heart disorder; disease phenotype; drug development; drug testing; gene therapy; genome editing; genome-wide; improved; individual variation; induced pluripotent stem cell; insight; leukemia; migration; nano-string; nerve stem cell; neurodevelopment; neurogenesis; novel; novel strategies; overexpression; relating to nervous system; stem cells; superoxide dismutase 1; tool; transcriptome; transcriptome sequencing

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.

摘要 唐氏综合症(DS)，或21三体，是导致儿童发育和认知障碍的主要遗传原因 孩子们。随着DS患者寿命的延长，我们现在意识到大多数人都会患上早发性阿尔茨海默病(AD)。 此外，DS患者极大地增加了患先天性心脏病、骨髓增生性疾病的风险 和白血病，以及免疫和其他系统缺陷。因此，理解正常的三个副本 21号染色体上的基因影响细胞表达谱，细胞表型不仅对DS很重要， 但对于折磨非DS人群的疾病，特别是AD，也许最大的医学挑战 我们的时代。研究人员试图确定导致该基因的转录和表型变化。 DS的各个方面；然而，这项工作受到个体差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 病理和基因途径是综合症的基础，并促进药物的筛选 改正它们。我们最近创建并演示了这样一个系统，并在令人信服的支持下 初步结果，建议用它来“解剖”21三体对全基因组通路的细胞影响 和表型，在未分化的多能干细胞和神经DS干细胞中。我们将利用这一独特的 研究21三体对特定基因表达的全基因组变化的最直接影响的系统 基因和通路(Aim1)，与特定的神经细胞表型变化(AIM2)相关，并最终 检测特定的chr21基因(目标3)在DS和AD病理中的作用。而不是专注于一个或多个 更“有利”的方面或假设，我们提出了一种不偏不倚和广泛的方法，得到了几个支持 在分子细胞生物学和神经生物学领域处于领先地位的合作者。这一新方法 有很大的希望来克服挑战，这些挑战混淆了对人的基本生物学的清楚理解 DS，从而为治疗DS的长期翻译努力提供了基础。更好地理解 人类DS中受干扰的基因和细胞通路对于药物治疗的发展(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，协调水平的基因组 整个基因组中的基因表达。