Zfp423 Mechanisms in Joubert Syndrome and Related Disorders
Zfp423 Joubert 综合征及相关疾病的机制
基本信息
- 批准号:10522573
- 负责人:
- 金额:$ 55.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:Animal GeneticsAnimal ModelAnimalsArchitectureBinding ProteinsBiological AssayBrainCRISPR interferenceCell LineageCell ProliferationCell modelCellsCerebellar vermis structureCiliaClinicalComplexConflict (Psychology)CuesCytoplasmic GranulesDataDefectDevelopmentDifferentiation AntigensDiseaseEnvironmentFamilyFrequenciesGene-ModifiedGenesGeneticGenetic TranscriptionHeterozygoteHomozygoteHumanIndividualInterventionJoubert syndromeLigandsMediatingModelingMolecular GeneticsMusMutant Strains MiceMutationNephronophthisisNeuronal DifferentiationNuclearOrganOutcomePathogenicityPathway interactionsPatientsPatternPhenotypePopulationProteinsRare DiseasesRegulator GenesReportingReproducibilityRetinoic Acid ReceptorRoleSHH geneSignal PathwaySignal TransductionStructureTestingTranscription Regulatory ProteinTretinoinUndifferentiatedVariantZinc Fingersbasebrain abnormalitiesbrain malformationciliopathydevelopmental diseasedevelopmental neurobiologyextracellulargenetic testinggranule cellhindbrainimprovedin vivoinnovationmalformationmorphogensmouse modelmutantnotch proteinprecursor cellprogenitorprogramsresponsesingle-cell RNA sequencingstem cellstooltranscription factor
项目摘要
Project Summary:
This project develops cell and animal models to understand the role of a multivalent transcription factor,
ZNF423, in integrating information from extracellular signaling and intracellular lineage pathways during
hindbrain development. ZNF423 encodes a constitutively nuclear transcriptional regulatory protein that
binds lineage differentiation factors of the EBF family and transcriptional effectors for canonical signling
pathways, including SMAD, retinoic acid, and NOTCH intracellular domains. ZNF423 mutations are
reported in rare Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) ciliopathy patients. The
ciliopathies comprise a broad family of individually rare disorders unified by signaling defects in
primary cilia. Clinical presentations range mild to lethal and from primary involvement of a single organ
to more pleiotropic presentations. The overwhelming majority of genes identified for ciliopathy disorders
encode physical components of primary cilia. Regulatory genes that control cilium-dependent
signaling and genetic modifiers that change the outcome of ciliary defects remain understudied with
respect to pathogenic mechanisms and potential points for intervention in more typical cases.
ZNF423 is thought to comprise an integrative node among several transcriptional complexes that
respond to classical intercellular signals during brain development and to regulate SHH signaling
through the primary cilium. Both reported patients and mouse models show hindbrain malformations
that include hypoplasia or agenesis of the vermis. Aim 1 will test hypotheses for ZNF423 activity in
canalizing information from complex signaling environments into predictable cell responses. Aim 2 will
comprehensively test for modifier genes that alter cellular outcomes ex vivo in response to loss of
ZNF423. Aim 3 will test hypotheses for ZNF423 participation in oligogenic brain malformations in a
well-validated animal model.
项目摘要:
该项目开发细胞和动物模型,以了解多价转录因子的作用,
ZNF 423,在整合来自细胞外信号传导和细胞内谱系途径的信息中,
后脑发育ZNF 423编码一个组成型核转录调控蛋白,
结合EBF家族的谱系分化因子和典型信号的转录效应子
途径,包括SMAD、视黄酸和NOTCH胞内结构域。ZNF423突变是
在罕见的Joubert综合征(JBTS 19)和肾单位萎缩症(NPHP 14)纤毛病变患者中报告。的
睫状体病包括一个广泛的家族的个别罕见的疾病统一的信号缺陷,
初级纤毛临床表现从轻度到致命,从单一器官的原发性受累
呈现出更多的多效性。绝大多数被鉴定为纤毛疾病的基因
编码初级纤毛的物理成分。控制纤毛依赖的调节基因
改变睫状体缺陷结果的信号传导和遗传修饰剂仍然研究不足,
关于致病机制和潜在的干预点,在更典型的情况下。
ZNF 423被认为在几个转录复合体中包含一个整合节点,
在大脑发育过程中响应经典的细胞间信号并调节SHH信号
穿过初级纤毛报告的患者和小鼠模型均显示后脑畸形
包括蚓部发育不全或发育不全目的1将测试ZNF 423活性的假设,
将复杂信号环境中的信息转化为可预测的细胞反应。目标2将
全面测试修饰基因,所述修饰基因响应于细胞因子的丧失而改变离体细胞结果。
ZNF 423。目的3将检验ZNF 423参与寡基因性脑畸形的假设,
良好的动物模型。
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)
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BRUCE A HAMILTON其他文献
BRUCE A HAMILTON的其他文献
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{{ truncateString('BRUCE A HAMILTON', 18)}}的其他基金
In situ proteomics for brain using genetically encoded probes.
使用基因编码探针进行大脑原位蛋白质组学。
- 批准号:
10707181 - 财政年份:2022
- 资助金额:
$ 55.27万 - 项目类别:
In situ proteomics for brain using genetically encoded probes.
使用基因编码探针进行大脑原位蛋白质组学。
- 批准号:
10576153 - 财政年份:2022
- 资助金额:
$ 55.27万 - 项目类别:
Zfp423 Mechanisms in Joubert Syndrome and Related Disorders
Zfp423 Joubert 综合征及相关疾病的机制
- 批准号:
9418651 - 财政年份:2017
- 资助金额:
$ 55.27万 - 项目类别:
Zfp423 Mechanisms in Joubert Syndrome and Related Disorders
Zfp423 Joubert 综合征及相关疾病的机制
- 批准号:
10620800 - 财政年份:2017
- 资助金额:
$ 55.27万 - 项目类别:
Synthetic Lethal Modifier of a New Ciliopathy Gene
新纤毛病基因的合成致死修饰剂
- 批准号:
8517755 - 财政年份:2012
- 资助金额:
$ 55.27万 - 项目类别:
Synthetic Lethal Modifier of a New Ciliopathy Gene
新纤毛病基因的合成致死修饰剂
- 批准号:
8655551 - 财政年份:2012
- 资助金额:
$ 55.27万 - 项目类别:
Synthetic Lethal Modifier of a New Ciliopathy Gene
新纤毛病基因的合成致死修饰剂
- 批准号:
8845563 - 财政年份:2012
- 资助金额:
$ 55.27万 - 项目类别:
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