Mechanisms of Revertant Mosaicism in Ichthyosis with Confetti
五彩纸屑鱼鳞病中回复性嵌合的机制
基本信息
- 批准号:10092126
- 负责人:
- 金额:$ 49.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-19 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAllelesApoptosisAreaBirthCRISPR screenCandidate Disease GeneCell CycleCell Cycle ProgressionCell Cycle StageCell NucleolusCell NucleusCellsChildhoodClinicalClonal ExpansionClustered Regularly Interspaced Short Palindromic RepeatsComet AssayCytosolDNA DamageDNA Double Strand BreakDNA RepairDNA lesionDevelopmentDiseaseDominant Genetic ConditionsEpidermisEventFrameshift MutationFrequenciesFundingGenesGeneticGenetic DiseasesGenetic RecombinationGrowthHaplotypesHistologicHumanIchthyosis en confettiImageIn VitroIndividualInheritedIntermediate FilamentsIslandKer10 proteinKeratinKineticsKnock-inKnock-outLeadLibrariesLoss of HeterozygosityMediatingMediator of activation proteinMitosisModelingMolecularMosaicismMusMutationNormal CellNormal tissue morphologyPathogenicityPathway interactionsPatientsProcessProteinsReporterResolutionRoleSelf-CorrectionSiteSkinSpottingsSystemTailTherapeuticTimeTissuescell behaviorcell typeexperimental studygenetic approachhomologous recombinationhuman diseasein vivointravital imagingkeratinocyteknock-downmouse modelmutantp53-binding protein 1pressurerecruitrepairedresponsesingle-cell RNA sequencingskin disordertooltwo-photon
项目摘要
PROJECT SUMMARY
Revertant mosaicism (RM) occurs from spontaneous, somatic correction of pathogenic mutation,
giving rise to areas of normal tissue. Ichthyosis with confetti (IWC), an autosomal dominant skin
disorder caused by mutations affecting the tail domains of keratin 10 (K10) and keratin 1 (K1), is
remarkable for its high frequency of RM, as patients develop hundreds to thousands of revertant
islands of normal skin beginning in childhood. Interestingly, each revertant clone arises from
independent copy-neutral loss-of-heterozygosity (CN-LOH), likely via homologous recombination
(HR) of the mutant haplotype. Furthermore, the revertant macules are observed to grow in size and
number over time, suggesting intercellular competition favoring the selection and expansion of
revertant clones over their mutant neighbors. We have successfully demonstrated that expression of
IWC mutant keratins uniquely increase the rate of HR, while inducing the formation of DNA double-
strand breaks (DSBs). Furthermore, we have developed a conditional knock-in model of IWC, which
clinically and histologically recapitulates disease including revertant mosaicism via CN-LOH, and
demonstrates expansion of revertant, wild type clones.
We now propose to systematically identify and interrogate the mechanisms and mediators governing
IWC keratin-induced HR and cellular competition. We will investigate which DNA damage response
(DDR) components are recruited to sites of keratin-induced DSBs, characterize the kinetics of DSB
formation and resolution, and pinpoint the stage in the cell cycle at which damage occurs. We
propose to utilize intravital live-imaging to explore, at the cellular level, whether altered rates of
mitosis, apoptosis, or differentiation/delamination underlie the intercellular competition in IWC. Finally,
we will perform single-cell RNA sequencing and CRISPR knockout screens, to identify mediators of
intercellular competition and determinants or modifiers of HR in IWC. We will further examine
compelling candidates in IWC patient and murine tissue and cells. Elucidating the previse
mechanisms of genetic reversion and intercellular competition in IWC has the potential to identify
pathways which may enable therapeutic recombination to treat inherited and acquired dominant
genetic disorders.
项目概要
回复嵌合体 (RM) 是由致病性突变的自发体细胞校正而产生的,
产生正常组织区域。伴有五彩纸屑的鱼鳞病 (IWC),一种常染色体显性皮肤病
由影响角蛋白 10 (K10) 和角蛋白 1 (K1) 尾部结构域的突变引起的疾病是
因其高频率的 RM 而引人注目,因为患者会出现数百至数千个回复突变
正常皮肤的岛屿从童年开始。有趣的是,每个回复克隆都来自
独立拷贝中性杂合性丢失(CN-LOH),可能通过同源重组
(HR) 突变单倍型。此外,观察到回复斑疹尺寸增大并且
随着时间的推移,数量不断增加,表明细胞间竞争有利于细胞的选择和扩张
回复性克隆优于其突变邻居。我们已经成功地证明了
IWC 突变角蛋白独特地提高 HR 速率,同时诱导 DNA 双链的形成
链断裂(DSB)。此外,我们还开发了IWC的条件敲入模型,
通过 CN-LOH 在临床和组织学上重现疾病,包括回复嵌合体,以及
展示回复野生型克隆的扩增。
我们现在建议系统地识别和询问管理机制和调解员
IWC 角蛋白诱导 HR 和细胞竞争。我们将研究哪种 DNA 损伤反应
(DDR) 成分被招募到角蛋白诱导的 DSB 位点,表征 DSB 的动力学
形成和解决,并查明损伤发生的细胞周期阶段。我们
提议利用活体实时成像在细胞水平上探索是否改变了
有丝分裂、细胞凋亡或分化/分层是 IWC 中细胞间竞争的基础。最后,
我们将进行单细胞 RNA 测序和 CRISPR 敲除筛选,以确定介导的
IWC 中细胞间竞争和 HR 的决定因素或调节因素。我们将进一步审查
IWC 患者和小鼠组织和细胞中引人注目的候选者。阐明前提
IWC 中的遗传逆转和细胞间竞争机制有可能确定
可能使治疗重组能够治疗遗传性和获得性显性遗传的途径
遗传性疾病。
项目成果
期刊论文数量(0)
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{{ truncateString('KEITH A CHOATE', 18)}}的其他基金
Genetics and Pathobiology of Cutaneous Mosaic Disorders
皮肤马赛克疾病的遗传学和病理学
- 批准号:
10376195 - 财政年份:2018
- 资助金额:
$ 49.05万 - 项目类别:
Genetics and Pathobiology of Disorders of Keratinization
角化疾病的遗传学和病理学
- 批准号:
10211211 - 财政年份:2015
- 资助金额:
$ 49.05万 - 项目类别:
Genetics and Pathobiology of Disorders of Keratinization
角化疾病的遗传学和病理学
- 批准号:
8942911 - 财政年份:2015
- 资助金额:
$ 49.05万 - 项目类别:
Genetics and Pathobiology of Disorders of Keratinization
角化疾病的遗传学和病理学
- 批准号:
10614377 - 财政年份:2015
- 资助金额:
$ 49.05万 - 项目类别:
Genetics and Pathobiology of Disorders of Keratinization
角化疾病的遗传学和病理学
- 批准号:
10371176 - 财政年份:2015
- 资助金额:
$ 49.05万 - 项目类别:
Pediatric Dermatology Research Alliance Annual Conference
小儿皮肤病学研究联盟年会
- 批准号:
8597492 - 财政年份:2013
- 资助金额:
$ 49.05万 - 项目类别:
Pediatric Dermatology Research Alliance Annual Conference
小儿皮肤病学研究联盟年会
- 批准号:
8723740 - 财政年份:2013
- 资助金额:
$ 49.05万 - 项目类别:
Mechanisms of Genetic Reversion in Ichthyosis With Confetti
五彩纸屑鱼鳞病的遗传逆转机制
- 批准号:
8703506 - 财政年份:2011
- 资助金额:
$ 49.05万 - 项目类别:
Mechanisms of Genetic Reversion in Ichthyosis With Confetti
五彩纸屑鱼鳞病的遗传逆转机制
- 批准号:
8332886 - 财政年份:2011
- 资助金额:
$ 49.05万 - 项目类别:
Mechanisms of Genetic Reversion in Ichthyosis With Confetti
五彩纸屑鱼鳞病的遗传逆转机制
- 批准号:
8219845 - 财政年份:2011
- 资助金额:
$ 49.05万 - 项目类别:
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