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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

基本信息

批准号：
10587752
负责人：
JEANNE Bentley LAWRENCE
金额：
$ 153.77万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-12 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587752
关键词：
Address Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Autoimmune Brain Cell Differentiation process Cell physiology Cells Child Chromosomal Duplication Chromosome 21 Chromosome abnormality Chromosomes Cilia Cognitive deficits Development Disease Down Syndrome Drug Targeting Early Onset Alzheimer Disease Endothelial Cells Equilibrium Funding Gene Cluster Gene Expression Genes Genetic Genome Hematopoietic Human Human Pathology In Vitro Individual Knowledge Life Medical Metabolic Methods Modeling Molecular Nerve Degeneration Neurons Organoids Pathogenesis Pathology Pathway interactions Persons Phenotype Population Predisposition Premature aging syndrome RNA RNA Interference Repression Resources Risk Role Signal Transduction System Testing Therapeutic Tissues Trisomy Untranslated RNA Variant Vascular System Viral Virus Diseases Work angiogenesis autism spectrum disorder cell type cognitive disability congenital heart disorder dosage drug development expectation gamma secretase genome-wide improved induced pluripotent stem cell innovation leukemia neurogenesis novel novel strategies overexpression response single-cell RNA sequencing stem cells tool transcriptome sequencing transcriptomics

项目摘要

ABSTRACT Down Syndrome (DS), or Trisomy 21 (T21), is a highly common cause of cognitive disability in children, and also impacts individuals throughout life, by increased risks of congenital heart disease, viral susceptibility, leukemia, and conditions such as metabolic, autoimmune and autism spectrum disorders. Furthermore, as individuals with DS live longer, we now know that most develop early-onset Alzheimer Disease (AD). Hence, understanding how three copies of tiny chromosome 21 elevates risks of conditions that afflict the non-DS population is broadly important, especially for the pressing medical challenge of AD. Identification of how T21 impacts specific certain cell-types to cause various aspects of DS has been hampered by variation between all people, and the genetic and phenotypic complexity of DS. Thus, a critical need is for improved ways to identify core effects of T21 on specific cell types and tissues, and the corresponding gene pathways involved. We have developed an inducible chromosome silencing system in DS iPS cells that allows a “reductionist” approach, keeping other variables constant while manipulating just chromosome 21 over-expression. In the first funding period, we validated the utility of this system to correct the known hematopoietic cell pathogenesis in DS and now have extended this to study neurogenesis and angiogenesis, which we will further investigate here. Our progress includes a major advance, as we have identified XIST “minigenes” which repress clustered genes in just a small chromosomal region, which we show for the “Down syndrome critical region”. This innovation has broad translational implications and will be used to in multiple ways, including in relation to APP and AD. One sub-aim will also test proof-of-principle of this approach for smaller chromosome duplication disorders, as in autism. Our main focus is to “dissect” the impact of T21 on genome-wide pathways and cell phenotypes, and distinguish ongoing functional effects in a given cell-type versus formation of different cell types. Our approach can define the immediate and direct effects of T21 over-expression, rather than marginal differences in tissues that have diverged in differentiation and pathology, and thus are far downstream of the root effects in cells. We will investigate what cells T21 impacts, when it impacts, and, critically, when effects are preventable or reversible. Such knowledge is key to inform targets for drug development. This work also may advance the longer-term prospects that “chromosome therapy” may eventually provide a therapeutic strategy. Finally, this work also has broad basic impact for understanding genome balance, the coordinated levels of expression for genes throughout the genome. .

摘要唐氏综合征（DS）或21三体（T21）是儿童认知障碍的一种非常常见的原因，也会影响个体的一生，增加先天性心脏病，病毒易感性，白血病和诸如代谢、自身免疫和自闭症谱系障碍的病症。此外如虽然患有DS的人寿命更长，但我们现在知道大多数人会发展为早发性阿尔茨海默病（AD）。因此，我们认为，了解微小的21号染色体的三个副本如何增加非DS患者的疾病风险人口的广泛重要性，特别是对于AD的紧迫医学挑战。如何识别T21 影响特定的某些细胞类型，导致DS的各个方面，人，以及DS的遗传和表型复杂性。因此，迫切需要改进方法， T21对特定细胞类型和组织的核心作用，以及相关的相应基因通路。我们有在DS iPS细胞中开发了一种可诱导的染色体沉默系统，该系统允许“还原论”方法，保持其他变量不变，同时仅操纵21号染色体的过表达。在第一次融资中期间，我们验证了该系统的实用性，以纠正已知的造血细胞发病机制，在DS和现在已经将其扩展到研究神经发生和血管生成，我们将在这里进一步研究。我们进展包括一个重大的进步，因为我们已经确定了XIST“小基因”，它抑制基因簇，只是一个很小的染色体区域，我们显示为“唐氏综合症关键区域”。这一创新广泛的翻译含义，并将用于多种方式，包括与APP和AD有关。一子目标还将测试这种方法用于较小的染色体复制障碍的原理证明，如自闭症我们的主要重点是“解剖”T21对全基因组途径和细胞表型的影响，区分给定细胞类型与不同细胞类型的形成中正在进行的功能效应。我们的方法可以定义T21过度表达的即时和直接影响，而不是组织中的边际差异它们在分化和病理学上有分歧，因此在细胞中的根效应的下游很远。我们将研究T21影响哪些细胞，何时影响，以及关键的是，何时影响是可以预防的，可逆的这些知识是为药物开发提供信息的关键。这项工作也可能促进从长远来看，“染色体疗法”可能最终提供一种治疗策略。最后这项工作也对理解基因组平衡，协调表达水平，整个基因组中的基因。 .