The Role of SPECC1L cytoskeletal protein in craniofacial development and malformation
SPECC1L细胞骨架蛋白在颅面发育和畸形中的作用
基本信息
- 批准号:9304185
- 负责人:
- 金额:$ 32.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-01 至 2021-06-30
- 项目状态:已结题
- 来源:
- 关键词:Adherens JunctionAdhesionsAffectAllelesAttenuatedBilateralBiological AssayBranchial arch structureCell AdhesionCell CommunicationCell DensityCell PolarityCell membraneCell physiologyCellsCephalicChemicalsCollaborationsComplexCongenital AbnormalityCraniofacial AbnormalitiesCultured CellsCytoskeletal ProteinsDataDefectDestinationsDiseaseEmbryoEmbryonic DevelopmentEpithelialExencephaliesExhibitsEyeFaceFamilyFutureGenesGeneticGoalsHumanImageIn VitroIntercellular JunctionsIowaJapanKnowledgeLinkLive BirthMeasuresMediatingMediationMedicalMembraneMesenchymalModelingMolecularMorphogenesisMovementMusMutateMutationNeural CrestNeural Crest CellNeural FoldNeural Tube ClosureNeural tubeNeuroectodermNeuroepithelialNeuroepithelial CellsOperative Surgical ProceduresOpitz syndromeOralOral cavityOrbital separation excessiveOutcomePalatePathogenesisPathway interactionsPatientsPerinatalPersonsPhenotypePlayPrevention strategyProductivityProto-Oncogene Proteins c-aktRoleSamplingServicesSeveritiesSignal TransductionStreamSyndromeTeebi syndromeTestingTherapeuticTissuesTransmission Electron MicroscopyUbiquitinationbasecell behaviorcell motilitycleft lip and palatecraniofacialcraniofacial developmentdensitydosageimprovedin vivoinhibitor/antagonistinsightlife time costmalformationmigrationmouse modelmutantneural platenew therapeutic targetnovelorofacial cleftpalatal shelvespalatogenesispostnatalsmall molecule
项目摘要
PROJECT SUMMARY
Orofacial clefts are among the most common birth defects in the U.S., occurring in 1/800 live-births. The
lifetime cost for medical treatment, educational services and lost productivity averages more than $100,000 per
affected person. While a number of contributory genes have been identified, there is a continued need to
understand the underlying pathogenetic mechanisms. We identified the first de novo mutations in a novel
cytoskeletal SPECC1L gene in patients with oblique facial clefts. Recent identification of SPECC1L mutations
in patients with syndromic and nonsyndromic cleft lip and palate suggests that insights into the cellular and
molecular mechanism of SPECC1L function will be directly relevant to both severe and common facial
malformations. Our data show that Specc1l is expressed in the neural folds at E8.5, including in pre-migratory
cranial neural crest cells (CNCCs). Later at E9.5, it is expressed in post-migratory CNCCs, and in the
branchial arches at E10.5. To study SPECC1L function, we have generated severe, hypomorphic and
conditional mouse alleles of Specc1l deficiency. The severe mouse allele is embryonic lethal at E9.5 with
defective neural tube (NT) closure and incomplete delamination of post-migratory CNCCs. The hypomorphic
allele shows incompletely penetrant perinatal exencephaly phenotype. Moderate mutants with one
hypomorphic and one severe allele show highly penetrant palate closure delay. In addition, SPECC1L-deficient
cells show altered adherens junctions (AJs) and reduced PI3K-AKT signaling, both in vitro in cultured cells and
in vivo in Specc1l mutant tissue. Modulation of cell-cell contacts is important not only for CNCC delamination
from the neuroectoderm, but also for “collective” migration of CNCCs to their defined destinations. The central
hypothesis of this project is that SPECC1L modulates cell adhesion and collective migration by regulating the
density of epithelial and mesenchymal cell-cell contacts through PI3K-AKT signaling. In Aim 1, we propose to
investigate the effect of Specc1l dosage on craniofacial development using our hypomorphic, severe, and
conditional mouse alleles. In Aim 2, we will investigate SPECC1L mediation of AJ stability and PI3K-AKT
signaling using small molecule modulators of PI3K-AKT pathway. We will also explore the mechanism
underlying SPECC1L mediation of AKT stability. In Aim 3, we will use live-imaging to quantitatively assess
changes in collective cell behavior. Analyses will be conducted in ex vivo cultured E8.5 neural plate explants,
with CNCCs marked with Wnt1-Cre or Sox10-Cre. Successful completion of these studies will establish novel
SPECC1L-based links between AJs, cell polarity and PI3K-AKT signaling during facial morphogenesis and
palate closure. Understanding the correlation between SPECC1L dosage or functional deficiency and
collective cell migration will provide targets for future therapeutic or preventative strategies against orofacial
clefting.
项目摘要
口面裂是美国最常见的出生缺陷之一,发生在1/800活产婴儿中。的
医疗、教育服务和生产力损失的终身成本平均超过10万美元,
受影响的人。虽然已经确定了许多贡献基因,但仍有必要继续
了解潜在的发病机制。我们在一个新的基因组中
面斜裂患者细胞骨架SPECC 1 L基因的研究SPECC 1 L突变的最新鉴定
综合征型和非综合征型唇腭裂患者的研究表明,
SPECC 1 L功能的分子机制将与严重和常见的面部疾病直接相关,
畸形我们的数据显示Specc 1 l在E8.5的神经褶皱中表达,包括在迁移前的神经褶皱中。
颅神经嵴细胞(CNCC)。随后在E9.5,它在迁移后CNCC中表达,并且在
鳃弓在E10.5。为了研究SPECC 1 L函数,我们生成了严重的,亚纯的,
Specc 1 l缺陷的条件性小鼠等位基因。重度小鼠等位基因在E9.5时具有胚胎致死性,
有缺陷的神经管(NT)闭合和迁移后CNCC的不完全分层。亚纯的
等位基因表现为不完全外显的围产期露脑表型。中度突变体,
亚型和一个严重等位基因显示高度渗透性腭闭合延迟。此外,SPECC 1 L缺陷型
无论是在体外培养的细胞中还是在体外培养的细胞中,细胞都显示出粘附连接(AJs)的改变和PI 3 K-AKT信号传导的减少
在Specc 11突变体组织中体内。细胞-细胞接触的调节不仅对于CNCC分层是重要的,
从神经外胚层,但也用于CNCC的“集体”迁移到其定义的目的地。中央
该项目的假设是SPECC 1 L通过调节细胞粘附和集体迁移来调节细胞粘附和集体迁移。
通过PI 3 K-AKT信号传导的上皮和间充质细胞-细胞接触的密度。在目标1中,我们建议
研究Specc 1 l剂量对颅面发育的影响,
条件小鼠等位基因。在目标2中,我们将研究SPECC 1 L介导的AJ稳定性和PI 3 K-AKT
使用PI 3 K-AKT途径的小分子调节剂进行信号传导。我们还将探讨机制
潜在的SPECC 1 L介导AKT稳定性。在目标3中,我们将使用实时成像来定量评估
集体细胞行为的变化。将在离体培养的E8.5神经板外植体中进行分析,
用Wnt 1-Cre或Sox 10-Cre标记的CNCC。成功完成这些研究将建立新的
基于SPECC 1 L的面部形态发生过程中AJs、细胞极性和PI 3 K-AKT信号传导之间的联系,
腭闭合了解SPECC 1 L剂量或功能缺陷与
集体细胞迁移将为未来针对口面的治疗或预防策略提供目标
裂缝
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)
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Irfan Saadi其他文献
Irfan Saadi的其他文献
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{{ truncateString('Irfan Saadi', 18)}}的其他基金
In utero rescue of cleft palate using maternal administration of folic acid
使用叶酸在子宫内挽救腭裂
- 批准号:
10646021 - 财政年份:2023
- 资助金额:
$ 32.51万 - 项目类别:
Investigating the protective effect of maternal Thm1 heterozygosity against cleft palate
母体 Thm1 杂合性对腭裂的保护作用研究
- 批准号:
10742414 - 财政年份:2023
- 资助金额:
$ 32.51万 - 项目类别:
The Role of SPECC1L cytoskeletal protein in craniofacial development and malformation
SPECC1L细胞骨架蛋白在颅面发育和畸形中的作用
- 批准号:
10213181 - 财政年份:2016
- 资助金额:
$ 32.51万 - 项目类别:
The Role of SPECC1L cytoskeletal protein in craniofacial development and malformation
SPECC1L细胞骨架蛋白在颅面发育和畸形中的作用
- 批准号:
9158833 - 财政年份:2016
- 资助金额:
$ 32.51万 - 项目类别:
Role of Cytoskeletal Protein SPECC1L in Facial Morphogenesis and Facial Clefting
细胞骨架蛋白 SPECC1L 在面部形态发生和面部裂隙中的作用
- 批准号:
8480396 - 财政年份:
- 资助金额:
$ 32.51万 - 项目类别:
Role of Cytoskeletal Protein SPECC1L in Facial Morphogenesis and Facial Clefting
细胞骨架蛋白 SPECC1L 在面部形态发生和面部裂隙中的作用
- 批准号:
8691932 - 财政年份:
- 资助金额:
$ 32.51万 - 项目类别:
Role of Cytoskeletal Protein SPECC1L in Facial Morphogenesis and Facial Clefting
细胞骨架蛋白 SPECC1L 在面部形态发生和面部裂隙中的作用
- 批准号:
8922036 - 财政年份:
- 资助金额:
$ 32.51万 - 项目类别:
Role of Cytoskeletal Protein SPECC1L in Facial Morphogenesis and Facial Clefting
细胞骨架蛋白 SPECC1L 在面部形态发生和面部裂隙中的作用
- 批准号:
8534223 - 财政年份:
- 资助金额:
$ 32.51万 - 项目类别:
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