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Signaling mechanisms underlying neural crest cell fate decisions

神经嵴细胞命运决定背后的信号机制

基本信息

批准号：
10908874
负责人：
ALEK G ERICKSON
金额：
$ 1.22万
依托单位：
KAROLINSKA INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10908874
关键词：
Affect Bar Codes Behavior Bioinformatics Biology CRISPR/Cas technology Cell Communication Cell Differentiation process Cell Lineage Cell Therapy Cell model Cells Cellular Structures Cephalic Characteristics Collaborations Communication Communities Conflict (Psychology)Congenital Disorders Data Data Set Decision Making Development Disease Disease Progression Dorsal Embryo Environment Event Face Failure Feedback Gene Delivery Genes Genetic Genetic Transcription Growth Guide RNA Heritability Human Imaging Techniques Individual Injections Lentivirus Ligands Light Location Logic Mammalian Genetics Maps Mediating Medical Research Mesenchymal Methods Microscopy Modeling Molecular Morphology Mus Mutate Neural Crest Neural Crest Cell Neural tube Neuroglia Outcome Pathology Pattern Peripheral Nervous System Pigments Population Positioning Attribute RNA library Regulation Research Sensory Shapes Signal Transduction Skeleton Statistical Models Structure Technology Testing Time Tooth structure Training Trees Validation blastomere structure cell behavior cell type combinatorial craniofacial craniofacial development design embryo cell experimental study improved in vivo innovation intercellular communication knock-down melanocyte microCT migration novel strategies population based post-doctoral training predictive modeling protein expression receptor response skeletal skills stem stem cell population stem cells success transcriptomics ultrasound viral gene delivery

项目摘要

The neural crest contributes a wide variety of cell types to the human face, giving rise to teeth, melanocytes, the craniofacial skeleton, and the peripheral nervous system. The diversification strategies used by the neural crest are still elusive, but seem to be highly sensitive to genetic perturbations because heritable diseases frequently disrupt neural crest development, which can impact craniofacial growth. Thus, clarifying how cell interactions bias neural crest cell fates could reveal mechanisms of disease progression, many of which remain obscure. To perform a systematic characterization of neural crest lineages and their developmental regulation by cell signaling, we have built upon our recent breakthroughs in single-cell transcriptomic analysis to include viral gene delivery for functional interrogation. Using barcode-based clonal lineage tracing and high- throughput genetic perturbations in vivo via ultrasound-guided injections of lentivirus into the forming cranial neural crest region, we will map how cell lineages interact and diversify to build the face. Based on our preliminary data, we hypothesize that neural crest cells utilize collective multipotency, and communicate via signaling interactions in the dorsal neural tube that balances molecular biasing of early neural crest cells towards fates in correct proportions. We will test this hypothesis by functional experiments targeting receptors and ligands in neural crest subpopulations, with special emphasis on genes that when mutated, can result in pathology. By assembling a global collaboration of experts in advanced imaging techniques, single-cell transcriptomics, and mammalian genetics, we will determine the disease mechanisms underlying failures in facial development, and in doing so, contribute valuable datasets for the craniofacial and neural crest biology communities. Successful completion of our research plan will illuminate potential avenues to manipulate the behavior of stem cells at the population-wide scale, and reveal how cell fate choices could be manipulated in specific locations in vivo to generate skeletal shape and form. This three- year postdoctoral training plan is an excellent opportunity for the candidate to train at a world-renowned medical research environment, while gaining a unique combination of skills, background and network that will make a clear path towards scientific independence.

神经脊为人脸提供了各种各样的细胞类型，产生了牙齿、黑素细胞、头面部骨骼和周围神经系统。神经所采用的多元化战略 CREST仍然难以捉摸，但似乎对遗传扰动高度敏感，因为可遗传疾病经常扰乱神经脊的发育，这可能会影响头面部的生长。因此，澄清细胞是如何相互作用偏向神经脊细胞命运可以揭示疾病进展的机制，其中许多仍然默默无闻。对神经脊谱系及其发育进行系统的描述通过细胞信号调节，我们建立在单细胞转录分析的最新突破之上包括用于功能性审讯的病毒基因传递。使用基于条形码的克隆血统追踪和高超声引导下将慢病毒注射到形成的颅骨中的体内遗传扰动神经脊区，我们将绘制细胞谱系如何相互作用和多样化，以建立面部。基于我们的初步数据，我们假设神经脊细胞利用集体多能性，并且通过背侧神经管中的信号相互作用进行沟通，以平衡分子偏见早期神经脊细胞以正确的比例朝向命运。我们将通过泛函来检验这一假设针对神经脊亚群中的受体和配体的实验，特别强调基因当发生突变时，会导致病理改变。通过召集高级专家的全球协作成像技术、单细胞转录组学和哺乳动物遗传学，我们将确定这种疾病面部发育失败的潜在机制，并通过这样做，为颅面和神经脊生物群落。我们的研究计划的成功完成将说明在种群范围内操纵干细胞行为的潜在途径，并揭示细胞如何命运的选择可以在体内的特定位置进行操纵，以产生骨骼形状和形状。这三个人- 一年的博士后培训计划是候选人在世界知名的医学研究环境，同时获得独特的技能、背景和网络组合，将为科学独立开辟一条清晰的道路。