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：
10438826
负责人：
JEANNE Bentley LAWRENCE
金额：
$ 55.85万
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10438826
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 21 Chromosome abnormality Chromosomes Complementary DNA Computational Biology Congenital chromosomal disease Development Developmental Biology Disease Dosage Compensation (Genetics)Down Syndrome Early Onset Alzheimer Disease 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 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 efficacy evaluation epigenetic silencing 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 translational potential

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愿景是开发“转化表观遗传学”尚未开发的潜力 XIST RNA 并促进对人类唐氏综合症的了解和潜在的治疗策略。 XIST/小鼠 Xist 编码一种独特的长非编码 RNA，具有诱导稳定的能力表观遗传沉默，顺式，而 XIST RNA 和 X 染色体剂量补偿的基本生物学是经过深入研究，我们的实验室正在努力开拓 XIST 剂量补偿的转化潜力常见的染色体失衡，特别是唐氏综合症仍然是一个主要的、人类遗传负担中未解决的部分，发生在 1/140 的出生中，如果这将“改变游戏规则”。携带 21 三体性的细胞中数百个基因的过度表达可以通过操纵来解决劳伦斯实验室最近在体外证明了一个大的 XIST cDNA 可以被准确地识别。插入一条 21 号染色体并诱导令人惊讶的全面、稳定的“三体沉默” 常染色体，显示于源自 DS 患者细胞的未分化 iPS 细胞中，我们现在正在寻求资金以建立基础。为实现下一个宏伟目标的近期进展奠定坚实的基础，以测试和制定长期目标；为此，我们将研究 XIST 介导的体内三体沉默的潜在发展。染色体沉默及其逆转或细胞减轻或生物体病理学的能力，在人脑中类器官和神经细胞以及经过充分研究的 DS 三体小鼠模型。我们的研究与阿尔茨海默病有直接关系，这种疾病几乎不可避免地会在 20-30 年内发生。通过将我们的一些目标集中在 APP 基因座上，我们将测试以下策略： APP 的靶基因治疗是插入 XIST 转基因进行染色体治疗的第一步。组建了一个由共同研究者和合作者组成的多学科团队，由两名互补的 PI 领导专业知识，我们将一起测试策略并探索 XIST RNA 提供的多功能性的全部潜力唐氏综合症和其他潜在疾病的“转化表观遗传学”工具。