Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome
Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome
批准号:
9789061
负责人:
JEANNE Bentley LAWRENCE
金额:
$57.13万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-19 至 2023-06-30
关键词:
AddressAlzheimer&aposs DiseaseAmyloid Beta A4 Precursor ProteinAreaBasic ScienceBiologyBirthBrain regionCell NucleusCellsCerebrumChromatinChromosome abnormalityChromosomesChromosomes, Human, Pair 21Complementary DNAComputational BiologyCongenital chromosomal diseaseDevelopmentDevelopmental BiologyDiseaseDosage Compensation (Genetics)Down SyndromeEmbryoEpigenetic ProcessFemaleFoundationsFundingGenesGenomeGoalsHumanHuman GeneticsImageIn VitroIndividualKnowledgeLinkMediatingMusNatureNeuronsOrganismOrganoidsPathologyPatientsPharmacotherapyPhenotypePositioning AttributePresenile Alzheimer DementiaPrincipal InvestigatorRNARegulationResearchResearch PersonnelSiteStructureTestingTherapeuticTherapeutic InterventionTimeTissuesTransgenesTranslational ResearchTrisomyUndifferentiatedUntranslated RNAVisionWorkX ChromosomeX Inactivationautosomebasedosagegene therapyin vivoin vivo evaluationinduced pluripotent stem cellinnovationinsightmouse modelmultidisciplinaryneurodevelopmentnoveloverexpressionrelating to nervous systemsuccesstool
中文摘要
摘要
这项研究的更广泛的视野是开发“转化表观遗传学”在很大程度上未开发的潜力
XIST RNA和先进的理解和唐氏综合症的潜在治疗策略。人类
XIST/小鼠Xist编码一种独特的长非编码RNA,其具有良好的诱导稳定表达的能力。
表观遗传沉默,顺式。虽然XIST RNA和X染色体剂量补偿的基本生物学是
经过大量研究,我们的实验室正在努力开拓XIST剂量补偿的转化潜力,
常见的染色体不平衡,尤其是唐氏综合症。染色体异常仍然是主要的,
人类遗传负担的未解决部分,发生在1/140的分娩中。这将是“改变游戏规则”,如果
在携带21三体的细胞中,数百个基因的过度表达可以通过操纵
一个基因XIST劳伦斯实验室最近在体外证明,一个大的XIST cDNA可以准确地表达。
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,显示在衍生自DS患者细胞的未分化iPS细胞中。我们现在寻求资金,
为追求下一个雄心勃勃的目标奠定了最近进展的坚实基础;测试和发展长期目标
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
类器官和神经细胞,并在一个充分研究的三体小鼠模型的DS。除了与DS的相关性外,
我们的研究与阿尔茨海默病直接相关,阿尔茨海默病几乎不可避免地发生,并且在20-30年内
唐氏综合症患者通过将我们的一些目标集中在APP基因座上,我们将测试一些策略,
APP靶向基因治疗是插入XIST转基因进行染色体治疗的第一步。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,由两名PI领导,
我们将共同测试策略,并探索XIST RNA提供多功能
唐氏综合症和其他潜在疾病的“转化表观遗传学”工具。
英文摘要
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.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome
-
批准号:10200106
-
项目类别:
-
资助金额:$55.99万
-
财政年份:2018
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome
-
批准号:9982390
-
项目类别:
-
资助金额:$56.99万
-
财政年份:2018
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Translational Epigenetics with XIST: Silencing Trisomy in Human Organoid and Mouse Models of Down Syndrome
-
批准号:10438826
-
项目类别:
-
资助金额:$55.85万
-
财政年份:2018
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
A Novel Approach to Molecular Cell Pathologies of Human Down Syndrome and DS-AD
-
批准号:10178060
-
项目类别:
-
资助金额:$40.13万
-
财政年份:2017
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation
-
批准号:10552441
-
项目类别:
-
资助金额:$62.84万
-
财政年份:2017
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
A Novel Approach to Molecular Cell Pathologies of Human Down Syndrome and DS-AD
-
批准号:9291367
-
项目类别:
-
资助金额:$41.93万
-
财政年份:2017
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
A Novel Approach to Molecular Cell Pathologies of Human Down Syndrome and DS-AD
-
批准号:10587752
-
项目类别:
-
资助金额:$153.77万
-
财政年份:2017
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
RNA and Genomic Junk in Fundamental Chromosome Architecture and Regulation
-
批准号:10174944
-
项目类别:
-
资助金额:$59.84万
-
财政年份:2017
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Introducing Cellular Aging in Human iPS Cells to Investigate Alzheimer Pathogenesis
-
批准号:9360939
-
项目类别:
-
资助金额:$209.38万
-
财政年份:2017
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Hematopoiesis in Down Syndrome iPS cells: Correction by Chromosome 21 Silencing
-
批准号:8761875
-
项目类别:
-
资助金额:$29.15万
-
财政年份:2014
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Hematopoiesis in Down Syndrome iPS cells: Correction by Chromosome 21 Silencing
-
批准号:9069836
-
项目类别:
-
资助金额:$29.15万
-
财政年份:2014
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
The repeat genome in interphase chromosome structure and regulation
-
批准号:8563193
-
项目类别:
-
资助金额:$31.28万
-
财政年份:2013
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
The repeat genome in interphase chromosome structure and regulation
-
批准号:9039486
-
项目类别:
-
资助金额:$31.83万
-
财政年份:2013
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Translating Dosage Compensation to Trisomy
-
批准号:8049267
-
项目类别:
-
资助金额:$250.71万
-
财政年份:2010
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?
-
批准号:7903514
-
项目类别:
-
资助金额:$12.3万
-
财政年份:2009
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Nuclear and Chromatin Packaging of Mammalian X-Chromosome
-
批准号:7910951
-
项目类别:
-
资助金额:$12.31万
-
财政年份:2009
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?
-
批准号:7666833
-
项目类别:
-
资助金额:$32.81万
-
财政年份:2008
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?
-
批准号:7516022
-
项目类别:
-
资助金额:$32.71万
-
财政年份:2008
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?
-
批准号:8115937
-
项目类别:
-
资助金额:$32.25万
-
财政年份:2008
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位:
Is Chromosome Therapy Possible for Down Syndrome and Other Karyotypic Imbalances?
-
批准号:7894683
-
项目类别:
-
资助金额:$32.57万
-
财政年份:2008
-
负责人:JEANNE Bentley LAWRENCE
-
依托单位: