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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：
10441269
负责人：
ALEK G ERICKSON
金额：
$ 6.06万
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/10441269
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 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 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.

神经嵴为人类面部提供了多种细胞类型，产生牙齿，黑色素细胞，颅面骨骼和周围神经系统。神经网络使用的多样化策略冠仍然难以捉摸，但似乎是高度敏感的遗传扰动，因为遗传性疾病，经常扰乱神经嵴的发育，这会影响颅面的生长。因此，阐明细胞如何影响神经嵴细胞命运的相互作用可以揭示疾病进展的机制，其中许多机制保持模糊。对神经嵴谱系及其发育进行系统表征通过细胞信号调节，我们建立在我们最近在单细胞转录组学分析的突破基础上，包括病毒基因传递功能的询问。使用基于条形码的克隆谱系追踪和高- 通过超声引导将慢病毒注射到形成中的颅骨中进行体内的通量遗传扰动神经嵴区域，我们将绘制细胞谱系如何相互作用和多样化来构建面部。基于我们初步数据，我们假设神经嵴细胞利用集体多能性，通过背侧神经管中的信号相互作用进行通信，早期神经嵴细胞以正确的比例走向命运。我们将通过函数检验这个假设。针对神经嵴亚群中受体和配体的实验，特别强调基因一旦发生突变，就会导致病理学通过召集全球专家合作，成像技术，单细胞转录组学和哺乳动物遗传学，我们将确定这种疾病面部发育失败的潜在机制，并在这样做的过程中，为面部发育提供了有价值的数据集。颅面和神经嵴生物群落我们的研究计划的成功完成将说明在人群范围内操纵干细胞行为的潜在途径，并揭示细胞是如何可以在体内的特定位置操纵命运选择以产生骨骼形状和形式。这三个- 一年的博士后培养计划是一个极好的机会，为候选人培养在世界知名的医学研究环境，同时获得技能，背景和网络的独特组合，为科学独立开辟一条清晰的道路。