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:9158833
- 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 PolarityCell membraneCell physiologyCell-Cell AdhesionCellsCephalicChemicalsCleaved cellCollaborationsComplexCongenital AbnormalityCraniofacial AbnormalitiesCultured CellsCytoskeletal ProteinsDataDefectDestinationsDiseaseEmbryoEmbryonic DevelopmentEpithelialExencephaliesExhibitsEyeFaceFamilyFutureGenesGeneticGoalsHumanImageIn VitroIntercellular JunctionsJapanKnowledgeLifeLinkLive BirthMeasuresMediatingMediationMedicalMembraneMesenchymalModelingMolecularMorphogenesisMovementMusMutateMutationNeural CrestNeural Crest CellNeural FoldNeural Tube ClosureNeural tubeNeuroectodermNeuroepithelialNeuroepithelial CellsOperative Surgical ProceduresOpitz syndromeOralOral cavityOrbital separation excessiveOutcomePalatePathogenesisPathway interactionsPatientsPerinatalPersonsPhenotypePlayPrevention strategyProductivityProteinsProto-Oncogene Proteins c-aktRoleSamplingServicesSeveritiesSignal TransductionStagingStreamTeebi 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.
项目总结
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:
9304185 - 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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