Transcription Factor 4 (TCF4) Regulation of Corneal Health
转录因子 4 (TCF4) 对角膜健康的调节
基本信息
- 批准号:10726628
- 负责人:
- 金额:$ 45.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgingAnimal ModelAutomobile DrivingBilateralBiologicalBiological AssayCell DensityCell LineCellular MorphologyCharacteristicsCloningClustered Regularly Interspaced Short Palindromic RepeatsCorneaCorneal DiseasesCorneal EndotheliumCorneal edemaDataDevelopmentDiagnosisDiseaseEndothelial CellsEpigenetic ProcessEuropeanEye diseasesFluorescent in Situ HybridizationFuchs&apos Endothelial DystrophyGenerationsGenesGeneticGenomicsHealthHeritabilityHeterozygoteKeratoplastyKnock-inKnock-in MouseLengthMediatingMedicalMethodsMicrosatellite RepeatsMinorityMusMutationNamesOlder PopulationOperative Surgical ProceduresPF4 GenePathogenesisPathway interactionsPatientsPhenotypePopulationPrimary Cell CulturesProceduresProtein IsoformsRNARegulationResearchResearch ProposalsSpecimenStressStudy modelsTestingTissuesToxic effectTransplantation SurgeryTrinucleotide Repeat ExpansionTrinucleotide RepeatsUnited StatesUntranslated RNAWorkcell immortalizationcellular developmentgenome wide association studygenomic locusimmunocytochemistryin vivo Modelinsightmouse modelnovelnovel therapeuticsrisk varianttherapeutic targettooltranscription factortranscriptome sequencing
项目摘要
PROJECT SUMMARY
Fuchs endothelial corneal dystrophy (FECD) is a bilateral, heritable degeneration of the corneal endothelium
that affects roughly 4% of the population older than 40 years in the United States. FECD is one of the most
common indications for corneal transplantation. Major advances in genomics have dramatically increased our
understanding of FECD, and identified diverse genetic and epigenetic causes and associations. In particular,
traditional linkage studies and GWAS studies identified an expanded CTG trinucleotide repeat (TNR)
expansion (named CTG18.1) in the non-coding region of transcription factor 4 (TCF4) gene as the most
strongly associated genetic alteration associated with late-onset FECD. The intronic TNR expansion within the
TCF4 gene is responsible for about 70% of FECD cases in European populations. Despite these substantial
advances made in identifying risk alleles and biological pathways that are involved in the development of
FECD, definitive treatment of FECD has mainly remained surgical with corneal transplantation. Effective
medical treatments for FECD are lacking. A major challenge in the field of FECD research is the absence of a
mouse model of the TCF4 repeat expansion. Mouse models have been developed for other genes associated
with FECD (COL8A2, Slc4a11) but these genes are responsible for only a minority of cases. Thus, current
models for studying TCF4 repeat expansion FECD include ex-vivo specimens, primary cell cultures, and
immortalized cell lines derived from tissue specimens obtained from patients with advanced FECD undergoing
corneal transplantation. An in vivo model of the TCF4 repeat expansion is needed, in particular one that could
be used to study early stage FECD. The main roadblock has been the challenge of creating animal models
with large uninterrupted repeats due to the technical difficulties. In preliminary studies, we have developed a
novel method for generating knock-in mouse models of trinucleotide repeat expansion disorders. Our unique
approach takes advantage of CRISPR and the highly efficient microhomology-mediated end joining (MMEJ) to
knock in trinucleotide repeats into gene loci. This approach has enabled us to knock in 338 CTG repeats into
the Tcf4 locus and successfully generate Tcf4-CTG338 knock-in heterozygous mice. Our overall objective is to
determine how the TCF4 repeat expansion contributes to FECD pathogenesis so that new therapeutics may
be developed. In our Specific Aims, we take two major strategies: characterize mice with a short TCF4 repeat
(338 repeats) that have already been generated and develop mice with a long TCF4 trinucleotide repeat (1,346
repeats) as repeat expansion length is correlated with corneal disease. We hypothesize that mice with a TCF4
repeat expansion can serve as an in vivo model for CTG expansion-mediated FECD. We anticipate that this
project will ultimately establish new insight into how a TCF4 repeat expansion contributes to FECD disease
and uncover promising therapeutic targets. More broadly, this work establishes a platform to develop novel
mouse models for the study of trinucleotide repeat expansion diseases.
项目总结
Fuchs内皮性角膜营养不良(FECD)是一种双侧可遗传的角膜内皮变性
这影响了美国约4%的40岁以上人口。FECD是世界上最大的
角膜移植的常见适应症。基因组学的重大进展极大地增加了我们的
对FECD的了解,并确定了不同的遗传和表观遗传原因和关联。特别是,
传统的连锁研究和GWAS研究发现了一个扩展的CTG三核苷酸重复序列(TNR)
扩增最多的是转录因子4(TCF4)基因的非编码区(命名为CTG18.1
与晚发性FECD密切相关的基因改变。内含子在TNR中的扩展
在欧洲人群中,约70%的FECD病例与TCF4基因有关。尽管有这些实质性的
在识别参与癌症发生的危险等位基因和生物途径方面的进展
FECD,FECD的最终治疗方法主要是角膜移植手术。有效
缺乏对FECD的医疗治疗。FECD研究领域的一个主要挑战是缺乏
小鼠模型TCF4重复扩张。其他相关基因的小鼠模型已经被开发出来
与FECD(COL8A2,SLC4a11)有关,但这些基因只对少数病例负责。因此,当前
研究TCF4重复扩增FECD的模型包括体外标本、原代细胞培养和
从晚期FECD患者的组织标本中获得永生化细胞系
角膜移植。需要TCF4重复扩增的体内模型,特别是可以
可用于早期FECD的研究。主要的障碍是建立动物模型的挑战
由于技术困难,具有大量不间断的重复。在初步研究中,我们开发了一种
建立三核苷酸重复扩增障碍敲入小鼠模型的新方法。我们独一无二的
该方法利用CRISPR和高效的微同源介导的末端连接(MMEJ)来
将三核苷酸重复序列敲入基因位点。这种方法使我们能够将338个CTG重复序列敲入
并成功构建了TCF4-CTG338敲入杂合子小鼠。我们的总体目标是
确定TCF4重复扩增在FECD发病机制中的作用,以便新的治疗方法可以
被开发出来。在我们的具体目标中,我们采取了两个主要策略:用短TCF4重复来表征小鼠
(338个重复),并培育出具有长TCF4三核苷酸重复(1,346)的小鼠
重复),因为重复扩展长度与角膜疾病相关。我们假设携带TCF4的小鼠
重复扩增可作为CTG扩增介导的FECD的体内模型。我们预计这将是
该项目最终将对TCF4重复扩增如何导致FECD疾病建立新的见解
并发现有希望的治疗靶点。更广泛地说,这部作品为小说的发展搭建了一个平台
研究三核苷酸重复扩张性疾病的小鼠模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Matilda F Chan其他文献
Matilda F Chan的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Matilda F Chan', 18)}}的其他基金
Analysis of chemical modulators for corneal endothelial dystrophies
角膜内皮营养不良的化学调节剂分析
- 批准号:
10487504 - 财政年份:2021
- 资助金额:
$ 45.2万 - 项目类别:
Analysis of chemical modulators for corneal endothelial dystrophies
角膜内皮营养不良的化学调节剂分析
- 批准号:
10661788 - 财政年份:2021
- 资助金额:
$ 45.2万 - 项目类别:
Analysis of chemical modulators for corneal endothelial dystrophies
角膜内皮营养不良的化学调节剂分析
- 批准号:
10304787 - 财政年份:2021
- 资助金额:
$ 45.2万 - 项目类别:
Regulation of Corneal Repair by Metalloproteinases
金属蛋白酶对角膜修复的调节
- 批准号:
8720005 - 财政年份:2013
- 资助金额:
$ 45.2万 - 项目类别:
Regulation of Corneal Repair by Metalloproteinases
金属蛋白酶对角膜修复的调节
- 批准号:
8579237 - 财政年份:2013
- 资助金额:
$ 45.2万 - 项目类别:
Regulation of Corneal Repair by Metalloproteinases
金属蛋白酶对角膜修复的调节
- 批准号:
9321195 - 财政年份:2013
- 资助金额:
$ 45.2万 - 项目类别:
The Role of Extracelluar Enzymes in Regulating Corneal Repair
细胞外酶在调节角膜修复中的作用
- 批准号:
8244501 - 财政年份:2008
- 资助金额:
$ 45.2万 - 项目类别:
The Role of Extracelluar Enzymes in Regulating Corneal Repair
细胞外酶在调节角膜修复中的作用
- 批准号:
7928523 - 财政年份:2008
- 资助金额:
$ 45.2万 - 项目类别:
The Role of Extracelluar Enzymes in Regulating Corneal Repair
细胞外酶在调节角膜修复中的作用
- 批准号:
8048007 - 财政年份:2008
- 资助金额:
$ 45.2万 - 项目类别:
The Role of Extracelluar Enzymes in Regulating Corneal Repair
细胞外酶在调节角膜修复中的作用
- 批准号:
7796608 - 财政年份:2008
- 资助金额:
$ 45.2万 - 项目类别:
相似海外基金
Impacts of hurricanes and social buffering on biological aging in a free-ranging animal model
飓风和社会缓冲对自由放养动物模型生物衰老的影响
- 批准号:
10781021 - 财政年份:2023
- 资助金额:
$ 45.2万 - 项目类别:
REU Site: Comparative Animal Model Approaches to Regeneration and Aging
REU 网站:再生和衰老的比较动物模型方法
- 批准号:
2243416 - 财政年份:2023
- 资助金额:
$ 45.2万 - 项目类别:
Continuing Grant
Early life trauma and aging using a long-lived animal model
使用长寿动物模型研究早期生命创伤和衰老
- 批准号:
10369990 - 财政年份:2022
- 资助金额:
$ 45.2万 - 项目类别:
Early life trauma and aging using a long-lived animal model
使用长寿动物模型研究早期生命创伤和衰老
- 批准号:
10550195 - 财政年份:2022
- 资助金额:
$ 45.2万 - 项目类别:
Programming amylin secretion to slow brain aging - an animal model
编程胰淀素分泌以减缓大脑衰老——动物模型
- 批准号:
9412623 - 财政年份:2017
- 资助金额:
$ 45.2万 - 项目类别:
Developing the Zebrafish as an animal model for aging
开发斑马鱼作为衰老动物模型
- 批准号:
6684675 - 财政年份:2003
- 资助金额:
$ 45.2万 - 项目类别:
Neurogenesis in an Animal Model of Cognitive Aging
认知衰老动物模型中的神经发生
- 批准号:
6532568 - 财政年份:2002
- 资助金额:
$ 45.2万 - 项目类别:
Neurogenesis in an Animal Model of Cognitive Aging
认知衰老动物模型中的神经发生
- 批准号:
6339639 - 财政年份:2001
- 资助金额:
$ 45.2万 - 项目类别:
Animal model for studying inner ear mechanism of aging
研究内耳衰老机制的动物模型
- 批准号:
12671674 - 财政年份:2000
- 资助金额:
$ 45.2万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




