Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome

XIST 的转化表观遗传学：沉默唐氏综合症人类类器官和小鼠模型中的三体性

基本信息

批准号：
9789061
负责人：
JEANNE Bentley LAWRENCE
金额：
$ 57.13万
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：
2018
资助国家：
美国
起止时间：
2018-09-19 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789061
关键词：
Address Alzheimer&apos s Disease Amyloid Beta A4 Precursor Protein Area Basic Science Biology Birth Brain region Cell Nucleus Cells Cerebrum Chromatin Chromosome abnormality Chromosomes Chromosomes, Human, Pair 21 Complementary DNA Computational Biology Congenital chromosomal disease Development Developmental Biology Disease Dosage Compensation (Genetics)Down Syndrome Embryo Epigenetic Process Female Foundations Funding Genes Genome Goals Human Human Genetics Image In Vitro Individual Knowledge Link Mediating Mus Nature Neurons Organism Organoids Pathology Patients Pharmacotherapy Phenotype Positioning Attribute Presenile Alzheimer Dementia Principal Investigator RNA Regulation Research Research Personnel Site Structure Testing Therapeutic Therapeutic Intervention Time Tissues Transgenes Translational Research Trisomy Undifferentiated Untranslated RNA Vision Work X Chromosome X Inactivation autosome base dosage gene therapy in vivo in vivo evaluation induced pluripotent stem cell innovation insight mouse model multidisciplinary neurodevelopment novel overexpression relating to nervous system success tool

项目摘要

ABSTRACT The broader vision of this research is to develop the largely unexplored potential for “translational epigenetics” of XIST RNA and advance understanding and a potential therapeutic strategy for Down Syndrome. Human XIST/mouse Xist encodes a unique long non-coding RNA with the well-established power to induce stable epigenetic silencing, in cis. While the basic biology of XIST RNA and X-chromosome dosage compensation is heavily studied, our lab is working to pioneer the translational potential of XIST dosage compensation for common chromosomal imbalances, particularly Down Syndrome. Chromosomal abnormalities remain a major, unaddressed part of the human genetic burden, occurring in 1/140 births. It would be “game-changing” if the over-expression of hundreds of genes in cells carrying trisomy 21 could be addressed by manipulation of just one gene, XIST. The Lawrence lab recently demonstrated in vitro that a large XIST cDNA could be accurately inserted into one chromosome 21 and induce surprisingly comprehensive, stable “trisomy silencing” of the autosome, shown in undifferentiated iPS cells derived from DS patient cells. We now seek funding to build on a strong foundation of recent progress in pursuit of the next ambitious goal; to test and develop the longer-term potential development for trisomy silencing in vivo. To this end, we will investigate XIST-mediated chromosomal silencing and its ability to reverse or mitigate cell or organism pathology, in human cerebral organoid and neural cells and in a well-studied trisomic mouse model of DS. In addition to relevance for DS, our studies have direct relevance for Alzheimer Disease, which occurs almost inevitably and 20-30 years in individuals with Down Syndrome. By focusing some of our goals on the APP locus, we will test strategies that target gene therapy for APP as a first step to insertion of XIST transgenes for chromosome therapy. We have assembled a multi-disciplinary team of co-investigators and collaborators, led by two PIs with complementary expertise, and together we will test strategies and probe the full potential that XIST RNA provides a versatile tool for “translational epigenetics” for Down Syndrome and potentially other conditions.

抽象的这项研究的更广泛的愿景是发展“翻译表观遗传学”的意外潜力 XIST RNA和提前理解以及唐氏综合症的潜在理论策略。人类 Xist/Mouse Xist编码具有诱导稳定的能力的独特的长无编码RNA 表观遗传沉默，顺式。而Xist RNA和X-Cromosomos剂量补偿的基本生物学是大量研究，我们的实验室正在努力开拓XIST剂量补偿的翻译潜力常见的染色体失衡，尤其是唐氏综合症。染色体异常仍然是主要的人类遗传燃烧的未解决部分，发生在1/140个出生中。如果是通过操纵公正可以解决携带三体术细胞中数百个基因的过表达一个基因，xist。劳伦斯实验室最近在体外证明了大型Xist cDNA可以准确插入一个21染色体中，并影响到令人惊讶的全面，稳定的“三体沉默” 常染色体，在未分化的IPS细胞中显示，该细胞衍生自DS患者细胞。我们现在寻求资金以建立在追求下一个雄心勃勃的目标方面的最新进展基础；测试和发展长期体内三体沉默的潜在发展。为此，我们将研究Xist介导的染色体沉默及其逆转或减轻细胞或生物病理学的能力，在人脑中器官和神经细胞，以及DS的精心培养的三体小鼠模型。除了与DS相关之外，我们的研究与阿尔茨海默氏病具有直接相关性，该疾病几乎不可避免地发生，在20 - 30年中患有唐氏综合症的人。通过将我们的一些目标集中在应用程序基因座上，我们将测试策略针对APP的靶向基因治疗是插入染色体疗法的Xist转基因的第一步。我们有组建了一个由共同研究者和合作者组成的多学科团队，由两个PIS领导专业知识，我们将共同测试策略，并探讨XIST RNA提供多功能的全部潜力用于唐氏综合症和可能其他情况的“翻译表观遗传学”的工具。