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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：
10016836
负责人：
VOLNEY L SHEEN
金额：
$ 26.25万
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 2023-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016836
关键词：
Address Alleles Animals Apoptosis Brain CRISPR/Cas technology Cell Death Cell Proliferation Cell physiology Cells Chromatin Chromosome 21 Chromosome Territory Chromosome abnormality Chromosomes 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.

总结唐氏综合征是由21号染色体上的一个基因子集（HSA21）的三倍体引起的。人士 DS均表现出一定程度的智力迟钝（MR）。MR已被归因于脑发育（即神经发生）受损以及细胞进行性死亡，突触发生（即神经变性）。三条HSA21染色体之一的沉默拯救了DS 但是这种治疗方法实际上受到基因组编辑的效率和能力的限制。专门针对单个HSA21染色体。我们的初步研究表明，改良的CRISPR方法大大增强了基因组材料在HSA 21上的整合，还设计了一种特异性靶向单个HSA21拷贝的方法。我们现建议实验以评估这些方法在人DS iPSC系中的效率，并遵循其结果。分化成神经和少突胶质细胞状态。我们还将讨论这些干预措施的程度与其同基因对应物相比，使DS系内的遗传和表观遗传表达正常化以及DS细胞是否从功能角度（增殖、细胞死亡、线粒体）得到拯救功能和氧化应激）。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学方法治疗DS（和其他染色体异常），并奠定基础潜在动物研究的基础。