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Mechanisms of Neural Crest Induction and Craniofacial Disorders

神经嵴诱导和颅面疾病的机制

基本信息

批准号：
10614427
负责人：
Shuo Wei
金额：
$ 37.22万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-17 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614427
关键词：
Address Affect Biological Markers CTNNB1 gene Clinical Congenital Abnormality Craniofacial Abnormalities Data Dental Development Diagnosis Disease Embryonic Development Etiology Functional disorder Genes Goals Human Impairment Intellectual functioning disability Knock-in Knowledge Lead Mediating Methods Modeling Monomeric GTP-Binding Proteins Morphogenesis Multipotent Stem Cells Mutation Neural Crest Neural Crest Cell Outcome Pathologic Pathway interactions Peripheral Nervous System Phosphorylation Phosphotransferases Prevention Prevention strategy Proto-Oncogene Proteins c-akt RNA Helicase Research Role Signal Transduction Signaling Molecule Study models Testing Text Tissues WNT Signaling Pathway Work Xenopus beta catenin craniofacial craniofacial disorder craniofacial structure craniofacial tissue de novo mutation diagnostic tool expectation feasibility testing gene function gene regulatory network human model insight mutant neural plate neurodevelopment neuromechanism neuroregulation novel novel diagnostics precise genome editing prevent stem cells tool transcription factor

项目摘要

Summary/Abstract Aberrant development of the multipotent neural crest (NC) cells can result in some of the most common birth defects called neurocristopathies, including malformations of craniofacial structures, dental tissues, and the peripheral nervous system. In humans, mutations in the RNA helicase DDX3 cause intellectual disability with multiple potential neurocristopathies; however, the function of DDX3 in NC development is unknown. In Xenopus tropicalis, a highly tractable model for studying NC development, depletion of DDX3 downregulates the AKT kinase activity and Wnt/beta-catenin signaling, leading to reduced NC induction. The goal of this application is to elucidate how DDX3 and downstream signaling molecules function in NC induction. The central hypothesis is that DDX3 induces the NC through a downstream gene regulatory network, whose components are critical for normal NC induction. This application has three specific aims. The first aim will determine how DDX3 induces the NC, with a focus on understanding how DDX3 activates AKT. The second aim will investigate the roles of AKT in NC induction downstream of DDX3, and the hypothesis to be tested is that AKT functions through Wnt/beta-catenin signaling. The third aim will test the feasibility of using X. tropicalis as a model to study how diseases-associated human mutations in DDX3 and downstream genes affect cell signaling and NC induction. Outcomes of this proposed research should provide new insight into the fundamental mechanisms governing NC induction, as well as the etiology of human neurocristopathies caused by mutations in multiple genes in this network.

摘要/文摘