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：
10065725
负责人：
ALEK G ERICKSON
金额：
$ 5.75万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10065725
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 Clone Cells Collaborations Communities Conflict (Psychology)Congenital Disorders Data Data Set Decision Making Development Disease Disease Progression Dorsal Embryo Environment Equilibrium 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 Ultrasonography Validation base blastomere structure cell behavior cell type combinatorial craniofacial craniofacial development design experimental study improved in vivo innovation intercellular communication knock-down melanocyte microCT novel strategies population based post-doctoral training predictive modeling protein expression receptor response skeletal skills stem stem cell population stem cells success transcriptomics 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rest为人脸贡献多种细胞类型，产生牙齿，黑色素细胞，颅面骨骼和周围神经系统。神经使用的多元化策略波峰仍然难以捉摸，但似乎对遗传扰动高度敏感，因为可遗传的疾病经常破坏神经rest发育，可能会影响颅面生长。因此，阐明细胞如何相互作用偏见神经rest细胞的命运可以揭示疾病进展的机制，其中许多保持晦涩。对神经rest谱系的系统表征及其发育通过细胞信号调节，我们已经建立在单细胞转录组分析中的最新突破之上包括病毒基因输送以进行功能询问。使用基于条形码的克隆谱系跟踪和高级通过超声引导的慢病毒注射体内吞吐量遗传扰动到形成颅骨神经rest区域，我们将绘制细胞谱系的相互作用和多样化以建立面部的方式。基于我们初步数据，我们假设神经rest细胞利用集体多履带，并且通过背面神经管中的信号相互作用进行通信，以平衡分子偏置的偏见早期的神经rest细胞以正确的比例朝着命运。我们将通过功能来检验该假设针对神经rest亚群中受体和配体的实验，特别强调基因突变后会导致病理。通过组建高级专家的全球合作成像技术，单细胞转录组学和哺乳动物遗传学，我们将确定该疾病面部开发中的失败基本机制，并为此，为宝贵的数据集提供了宝贵的数据集颅面和神经rest生物学社区。成功完成我们的研究计划将阐明潜在的途径以在人口范围内操纵干细胞的行为，并揭示细胞的方式可以在体内特定位置操纵命运选择，以产生骨骼形状和形式。这个三一年的博士后培训计划是候选人在世界知名的训练的绝佳机会医学研究环境，同时获得了技能，背景和网络的独特组合走向科学独立性。