The Role of GPR161 in the Etiology of Neural Tube Defects
GPR161 在神经管缺陷病因学中的作用
基本信息
- 批准号:10424509
- 负责人:
- 金额:$ 38.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdultAdverse effectsAffectApoptosisBiochemicalBiological AssayBiological ModelsCRISPR/Cas technologyCandidate Disease GeneCell Culture SystemCell LineCell PolarityCell ProliferationCell modelCell physiologyCellsCellular MorphologyCephalicChildComplexCongenital AbnormalityCraniofacial AbnormalitiesCritical PathwaysCystCytoskeletonDataDefectDevelopmentEmbryoEmbryonic DevelopmentEnvironmental Risk FactorEtiologyFailureFamilyGene ExpressionGenerationsGenesGeneticGenetic EpistasisHaploidyHumanImpairmentIn VitroInfantInterventionKnock-inKnock-in MouseKnock-outKnockout MiceLaboratoriesLeadLinkMapsMeasuresModelingMolecularMorphogenesisMusNeural Crest CellNeural Tube ClosureNeural Tube DefectsNeural tubeNeuroepithelialPartner in relationshipPatientsPatternPhenotypePredispositionProcessProteomicsResearchReverse Transcriptase Polymerase Chain ReactionRiskRoleSignal PathwaySignal TransductionSignaling MoleculeSignaling ProteinStructural Congenital AnomaliesSystemTechnologyTestingVariantandrogenicbasecell motilitycohortconditional knockoutcraniofacial developmentdevelopmental geneticsembryonic stem cellgene networkgenetic variantgenome editinggenome sequencingimprovedin vivoin vivo Modelmalformationmigrationmouse modelnerve stem cellnestin proteinnovelnovel therapeutic interventionpolarized cellprogramsrare variantrisk variantstem cell proliferationstem cellstreatment strategywhole genome
项目摘要
ABSTRACT
Neural tube defects (NTDs) are the second most common human structural birth defect. They result from the
failure of neural tube closure (NTC) during neurulation. There are multiple developmentally-related signaling
pathways involved as NTC processes spatially and temporally. The causes of NTDs are known to be multi-
factorial, including genetic and environmental factors. Given that the genetic factors contribute significantly to
the etiology of NTDs, the identification of specific gene variants and the characterization of their underlying
molecular and cellular mechanisms leading to the etiology of NTDs has progressed slowly over the last several
decades. We have identified novel rare variants of GPR161 using whole genome sequencing (WGS) from large
human cohorts. GPR161 is a known negative regulator of the Shh signaling pathway, and Shh null mice express
NTD phenotypes. The GPR161vl and null mice models suggest the involvement of other signaling pathways. The
Shh, Wnt and PCP signaling pathways are involved in the neural tube patterning, neural stem cell proliferation,
and neural crest cell migration via cell polarization during NTC. We will test the following specific hypothesis with
in vitro and in vivo models. (1) GPR161 can regulate Wnt and PCP signaling pathways, and the novel rare gene
variants of GPR161 adversely impact these signaling pathways, which dysregulate NTC. (2) GPR161 can impact
cell proliferation and cell polarity via Wnt and PCP signaling, respectively, thus the NTD variants of GPR161 will
increase NTD susceptibility by compromising these processes. (3) The identified human GPR161 NTD variants,
alone or in combination with other PCP genes, will produce NTD phenotypes in knock in (KI) mouse models.
The proposed research program will provide the novel molecular, cellular, developmental and genetic links
between GPR161, Wnt and PCP signaling pathways, as they relate to morphogenetic processes involved in
normal NTC. Filling this large datagap can lead us to novel therapeutic strategies for both intervention and
treatment.
摘要
神经管缺陷(NTD)是人类第二常见的结构性出生缺陷。它们是由
神经管闭合(NTC)失败。有多种与发育相关的信号
NTC在空间和时间上所涉及的通路。已知NTDS的原因是多方面的-
因素,包括遗传和环境因素。考虑到遗传因素对
神经管畸形的病因、特定基因变异的鉴定及其潜在的特征
在过去几年中,导致NTDS病因的分子和细胞机制进展缓慢
几十年。我们使用全基因组测序(WGS)从大样本中鉴定了GPR161的新的稀有变体
人类群体。GPR161是已知的Shh信号通路的负调控因子,Shh缺失的小鼠表达
NTD表型。GPR161vl和空小鼠模型表明,其他信号通路也参与其中。这个
Shh、Wnt和PCP信号通路参与了神经管构型、神经干细胞增殖、
在NTC期间,神经脊细胞通过细胞极化迁移。我们将使用以下特定假设来测试
体外和体内模型。(1)GPR161可调控Wnt和PCP信号通路,新发现的稀有基因
GPR161的变异体对这些信号通路产生不利影响,使NTC失控。(2)GPR161可以影响
细胞增殖和细胞极性分别通过Wnt和PCP信号,因此GPR161的NTD变体将
通过损害这些过程来增加NTD的易感性。(3)已鉴定的人类GPR161 NTD变异体,
单独或与其他PCP基因结合,将在敲入(KI)小鼠模型中产生NTD表型。
拟议的研究计划将提供新的分子、细胞、发育和遗传联系
在GPR161、Wnt和PCP信号通路之间,因为它们与参与的形态发生过程有关
全国过渡委员会正常。填补这个大的数据缺口可以引导我们找到新的治疗策略,既可以进行干预,也可以
治疗。
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)
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RICHARD H. FINNELL其他文献
RICHARD H. FINNELL的其他文献
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{{ truncateString('RICHARD H. FINNELL', 18)}}的其他基金
Understanding Genetic Complexity in Spina Bifida
了解脊柱裂的遗传复杂性
- 批准号:
10750235 - 财政年份:2023
- 资助金额:
$ 38.29万 - 项目类别:
12th International Conference on Neural Tube Defects
第十二届国际神经管缺陷会议
- 批准号:
10469136 - 财政年份:2022
- 资助金额:
$ 38.29万 - 项目类别:
Role of Slc25a32 and Its Interaction with Lrp6 in the Etiology of Neural Tube Defects
Slc25a32 的作用及其与 Lrp6 的相互作用在神经管缺陷病因学中的作用
- 批准号:
10355528 - 财政年份:2020
- 资助金额:
$ 38.29万 - 项目类别:
MicroRNA regulation of neural tube closure
MicroRNA对神经管闭合的调节
- 批准号:
10570194 - 财政年份:2020
- 资助金额:
$ 38.29万 - 项目类别:
Role of Slc25a32 and Its Interaction with Lrp6 in the Etiology of Neural Tube Defects
Slc25a32 的作用及其与 Lrp6 的相互作用在神经管缺陷病因学中的作用
- 批准号:
10577749 - 财政年份:2020
- 资助金额:
$ 38.29万 - 项目类别:
MicroRNA regulation of neural tube closure
MicroRNA对神经管闭合的调节
- 批准号:
10352211 - 财政年份:2020
- 资助金额:
$ 38.29万 - 项目类别:
Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality
使用布里渊-OCT 多模态进行神经管发育的生物力学
- 批准号:
9770703 - 财政年份:2018
- 资助金额:
$ 38.29万 - 项目类别:
Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality
使用布里渊-OCT 多模态进行神经管发育的生物力学
- 批准号:
10194569 - 财政年份:2018
- 资助金额:
$ 38.29万 - 项目类别:
Biomechanics of Neural Tube Development using Brillouin-OCT Multimodality
使用布里渊-OCT 多模态进行神经管发育的生物力学
- 批准号:
10551412 - 财政年份:2018
- 资助金额:
$ 38.29万 - 项目类别:
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