Function of IRF6 in regulating E-cadherin dependent adherens junctions
IRF6在调节E-钙粘蛋白依赖性粘附连接中的功能
基本信息
- 批准号:10534114
- 负责人:
- 金额:$ 1.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-12-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdherens JunctionAdhesionsAffectAlternative TherapiesBindingBinding ProteinsBiochemicalCell AdhesionCell Adhesion MoleculesCell LineCell membraneCell-Cell AdhesionCellsCellular AssayCytoplasmDNA BindingDNA Binding DomainDataDefectE-CadherinEngineered skinExcisionExocytosisFamilyFinancial HardshipGenetic TranscriptionGoalsGuanosine Triphosphate PhosphohydrolasesHealth Care CostsIn VitroIntercellular JunctionsInterferonsMembraneMolecularMovementMutationN-terminalNME1 geneOperative Surgical ProceduresPathway interactionsPatientsPersonsProcessProliferatingProteinsRegulationRoleSurgical complicationTestingTissue EngineeringTreatment CostUnited StatesWorkcell motilityimprovedinsightkeratinocytekeratinocyte differentiationmembermigrationmutantnovelprotein protein interactionsurgical riskthree-dimensional modelingtissue repairtraffickingtranscription factorvirtualwoundwound carewound healing
项目摘要
PROJECT SUMMARY
Over 70 million surgeries are performed in the United States annually. Although many wounds heal without
problem, half require postsurgical wound care. Wounds that do not heal affect about 7 million people annually
and generate treatment costs of about $100 billion, which creates a significant financial burden on the US
economy. Increasing our understanding of the molecular pathways regulating wound healing would enhance
tissue repair and reduce healthcare costs.
Our long-term goal is to identify molecular pathways regulating tissue repair. We previously demonstrated
that the transcription factor Interferon Regulatory Factor 6 (IRF6) is required for proper wound healing by acting
as a master regulator of keratinocyte differentiation, proliferation, and collective cell migration. Our recent
preliminary data show that Irf6-deficient keratinocytes have weaker cell-cell adhesion, and reduced membrane
localization of adherens junction components, including E-cadherin, providing a potential rationale for the IRF6-
dependent keratinocyte migration defect. Interestingly, our preliminary data also revealed that total adherens
junction protein levels were not changed, suggesting a non-transcriptional function of IRF6 in these processes.
IRF6, as a member of the Interferon regulatory transcription factor family, contains a highly conserved N-
terminal, DNA-binding domain, and a less conserved protein interaction domain. Most of IRF6 described
functions have been associated with its transcriptional activity, and very little is known about the functions of its
protein interaction domain. Particularly, which domain of IRF6 contributes to cell-cell adhesions required for
wound healing, is unknown. Our central hypothesis is that IRF6 promotes collective cell migration via a non-
transcriptional regulation of cell-cell adhesion molecules at the cytoplasmic membrane. We will test our central
hypothesis with the execution of two aims. In Aim 1 we will determine how IRF6 regulates E-cadherin trafficking.
In Aim 2 we will determine how IRF6 promotes collective cell migration. To test our hypothesis, using a wide
range of biochemical and cellular assays, we will take advantage of multiple IRF6 mutant lines to determine
which domains of this transcription factor are required for regulating cell adhesions. The same mutant cell lines
will be used to perform scratch wounds in 2D and excisional wounds in 3D models which will shed light on the
importance of each domain of IRF6 in collective cellular migration.
At the completion of this study, we will have identified a novel mechanism by which this transcription factor
regulates vesicular trafficking necessary for cell adhesion organization, which could provide a molecular
mechanism for the increased risk of surgical complications observed in patients with IRF6 mutations.
项目概要
美国每年进行超过 7000 万例手术。尽管许多伤口不愈合
问题中,一半需要术后伤口护理。每年约有 700 万人受到无法愈合的伤口影响
产生约1000亿美元的治疗费用,给美国造成沉重的财政负担
经济。增加我们对调节伤口愈合的分子途径的了解将增强
组织修复并降低医疗费用。
我们的长期目标是确定调节组织修复的分子途径。我们之前演示过
转录因子干扰素调节因子 6 (IRF6) 是伤口正常愈合所必需的
作为角质形成细胞分化、增殖和集体细胞迁移的主要调节剂。我们最近的
初步数据表明,Irf6缺陷的角质形成细胞的细胞间粘附力较弱,细胞膜减少
粘附连接成分(包括 E-钙粘蛋白)的定位,为 IRF6- 提供了潜在的原理
依赖性角质形成细胞迁移缺陷。有趣的是,我们的初步数据还显示,总依从者
连接蛋白水平没有改变,表明 IRF6 在这些过程中具有非转录功能。
IRF6作为干扰素调节转录因子家族的一员,含有高度保守的N-
末端、DNA 结合结构域和不太保守的蛋白质相互作用结构域。大多数 IRF6 描述
功能与其转录活性相关,但对其功能知之甚少。
蛋白质相互作用域。特别是,IRF6 的哪个结构域有助于细胞间粘附
伤口愈合情况,未知。我们的中心假设是IRF6通过非-促进集体细胞迁移
细胞质膜上细胞间粘附分子的转录调节。我们将测试我们的中央
执行两个目标的假设。在目标 1 中,我们将确定 IRF6 如何调节 E-钙粘蛋白运输。
在目标 2 中,我们将确定 IRF6 如何促进集体细胞迁移。为了检验我们的假设,使用广泛的
一系列生化和细胞测定,我们将利用多个 IRF6 突变系来确定
该转录因子的哪些结构域是调节细胞粘附所必需的。相同的突变细胞系
将用于执行 2D 模型中的划伤和 3D 模型中的切除伤口,这将有助于揭示
IRF6 每个结构域在集体细胞迁移中的重要性。
这项研究完成后,我们将确定一种新的机制,通过该机制该转录因子
调节细胞粘附组织所需的囊泡运输,这可以提供分子
IRF6 突变患者中观察到的手术并发症风险增加的机制。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
To Stick or Not to Stick: Adhesions in Orofacial Clefts.
粘还是不粘:口面部裂隙粘连。
- DOI:
- 发表时间:2022-01-18
- 期刊:
- 影响因子:4.2
- 作者:Antiguas, Angelo;Paul, Brian J;Dunnwald, Martine
- 通讯作者:Dunnwald, Martine
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{{ truncateString('Anyelo Antiguas', 18)}}的其他基金
Function of IRF6 in regulating E-cadherin dependent adherens junctions
IRF6在调节E-钙粘蛋白依赖性粘附连接中的功能
- 批准号:
10312856 - 财政年份:2021
- 资助金额:
$ 1.84万 - 项目类别:
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