Epigenetic Silencing of HSA21 in Down Syndrome

唐氏综合症中 HSA21 的表观遗传沉默

基本信息

批准号：
9892127
负责人：
VOLNEY L SHEEN
金额：
$ 21.88万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892127
关键词：
Address Alleles Animals Apoptosis Brain CRISPR/Cas technology Cell Death Cell Proliferation Cell physiology Cells Chromatin Chromosome Territory Chromosome abnormality Chromosomes Chromosomes, Human, Pair 21 Clustered Regularly Interspaced Short Palindromic Repeats Code Complex DNA Methylation Data Defect Development Disease Down Syndrome Early Intervention Embryonic Development Epigenetic Process Exonuclease Foundations Functional disorder Future Gene Expression Gene Silencing Generations Genes Genetic Genetic Diseases Genetic Nondisjunction Genetic Recombination Genetic Transcription Genomics Genotype Human Impairment In Vitro Individual Intervention Knock-in Lead Live Birth Location Longevity Maintenance Meiosis Mental Retardation Messenger RNA Methylation MicroRNAs Mitochondria Nerve Degeneration Neurocognitive Deficit Neurologic Oligodendroglia Open Reading Frames Oxidative Stress Pathologic Pathway interactions Pharmacology Phenotype Pluripotent Stem Cells Polycomb Presenile Alzheimer Dementia Proliferating Proteins Seizures Sex Chromatin Signal Transduction Single Nucleotide Polymorphism Single-Stranded DNA Site Specificity Testing Therapeutic Therapeutic Intervention Transcript Transgenes Trisomy Untranslated RNA Work X Chromosome X Inactivation autosome ds-DNA experimental study gene function genome editing genome-wide induced pluripotent stem cell nerve stem cell neurogenesis novel novel strategies optimal treatments progenitor recruit relating to nervous system repaired synaptogenesis

项目摘要

Summary Down syndrome arises from the triplication of a subset of genes on chromosome 21 (HSA21). Individuals with DS uniformly demonstrate some degree of mental retardation (MR). The MR has been attributed to impairments in brain development (i.e. neurogenesis) as well as progressive cell death with altered synaptogenesis (i.e. neurodegeneration). Silencing of one of the three HSA21 chromosomes rescues the DS phenotype but such a therapeutic approach is limited practically by the efficiency of genomic editing and ability to specifically target a single HSA21 chromosome. Our preliminary studies show the feasibility of a novel modified CRISPR approach which greatly enhances the integration of genomic material on HSA21 and we have also devised a means with which to specifically target a single HSA21 copy. We now propose experiments to assess the efficiency of these approaches in human DS iPSC lines and following their differentiation into neural and oligodendrocyte states. We will also address to what extent these interventions normalize both genetic and epigenetic expression within the DS lines compared to their isogenic counterparts and whether the DS cells are rescued from a functional perspective (proliferation, cell death, mitochondrial function and oxidative stress). Overall, if successful, these studies will overcome two fundamental hurdles needed to treat DS (and other chromosomal abnormalities) from an epigenetic approach and lay the foundation for potential animal studies.

概括唐氏综合症源于染色体21（HSA21）上的一部分基因的三分一式定序。有个人 DS均匀地表现出一定程度的智力障碍（MR）。 MR被归因于大脑发育障碍（即神经发生）以及随着改变的渐进细胞死亡突触发生（即神经变性）。沉默的三个HSA21染色体之一拯救了DS 表型但这种治疗方法实际上受到基因组编辑和能力的效率的限制专门针对单个HSA21染色体。我们的初步研究表明了小说的可行性修改了CRISPR方法，可以极大地增强基因组材料在HSA21上的整合，我们还设计了一种专门针对单个HSA21副本的手段。我们现在建议实验以评估人类DS IPSC线中这些方法的效率并遵循其效率分化为神经和少突胶质细胞状态。我们还将在多大程度上解决这些干预措施与它们的同源物相比以及是否从功能的角度挽救DS细胞（增殖，细胞死亡，线粒体功能和氧化应激）。总的来说，如果成功，这些研究将克服两个基本障碍需要从表观遗传方法中治疗DS（和其他染色体异常）并放置潜在动物研究基金会。