Characterization of the cellular and molecular mechanisms that mediate glial tiling

介导神经胶质平铺的细胞和分子机制的表征

基本信息

批准号：
10645080
负责人：
Sarah C Kucenas
金额：
$ 34.72万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645080
关键词：
Apoptosis Axon Behavior Candidate Disease Gene Cell Communication Cells Central Nervous System Central Nervous System Degenerative Diseases Clustered Regularly Interspaced Short Palindromic Repeats Collection Color Cues Data Development Diagnosis Disease Dorsal Electron Microscopy Event Extracellular Matrix Future Genes Genome Image Injury Location Mediating Mediator Modification Molecular Motor Motor Neurons Myelin Nature Nervous System Neuroglia Oligodendroglia Peripheral Nervous System Physiological Population Positioning Attribute Process Proliferating Radial Receptor Signaling Resources Schwann Cells Specific qualifier value Spinal Spinal Cord Spinal nerve structure System Transgenic Organisms Vertebral column Zebrafish cell behavior genetic manipulation gliogenesis in vivo insight migration model organism neural novel oligodendrocyte progenitor pharmacologic screening small molecule stem cells

项目摘要

Development of a functional and efficient nervous system requires the orchestrated specification, migration and differentiation of glia. During gliogenesis in both the central and peripheral nervous systems (CNS and PNS, respectively), large populations of glia are specified that must migrate and differentiate into not only functional glial cells, but also coordinate their development so that they occupy discrete, non-overlapping territories with neighboring glia. This phenomenon of glial spacing, or tiling, can occur between glia found in the CNS, PNS, or between glial cells where one cell resides in the CNS and the other resides in the PNS. Although we know that these tiling events occur, we don’t know the molecular nature of these interactions or whether they are used by all tiling glia. Additionally, how local glial-glial interactions play a role in global glial tiling is unknown. In this proposal, using zebrafish as a model organism, we will investigate the cellular and molecular mechanisms that mediate pre-myelinating glial tiling at motor exit point (MEP) transition zones (TZ) and in the developing spinal cord. In Aim 1 of this project, we will use a combination of expression analysis, multi-color, in vivo, time-lapse imaging, electron microscopy, pharmacological and genetic manipulation (CRISPR) of newly identified mediators to elucidate the cellular and molecular mechanisms that govern myelinating glial tiling at MEP TZs. In Aim 2, we will determine if the same mechanisms we characterize in Aim 1 also mediate tiling between oligodendrocyte progenitor cells (OPC) in the developing spinal cord. To better understand, diagnose and treat the many degenerative disorders of the CNS and PNS, we need to comprehend the cellular and molecular mechanisms that mediate glial-glial interactions and tiling. Zebrafish provide a unique opportunity to directly observe and manipulate cell populations to gain insight into how glial cells interact under normal physiological conditions, and if those interactions that ultimately result in glial tiling are perturbed in disease.

功能性和高效的神经系统的发展需要精心策划的规范、迁移和中枢神经系统和周围神经系统（CNS 和 PNS）的胶质细胞分化过程中。分别），大量的神经胶质细胞被指定必须迁移并分化为不仅是功能性的神经胶质细胞，而且还协调它们的发育，使它们占据离散的、不重叠的区域这种神经胶质间隔或平铺现象可能发生在 CNS、PNS 或神经胶质细胞之间。神经胶质细胞之间，一个细胞位于 CNS，另一个细胞位于 PNS。这些平铺事件发生时，我们不知道这些相互作用的分子性质，也不知道它们是否被使用此外，局部神经胶质-神经胶质相互作用如何在全局神经胶质平铺中发挥作用尚不清楚。建议，使用斑马鱼作为模式生物，我们将研究细胞和分子机制介导运动出口点 (MEP) 过渡区 (TZ) 和发育中脊柱的髓鞘形成前神经胶质平铺在这个项目的目标1中，我们将结合表达分析、多色、体内、延时。新发现的介质的成像、电子显微镜、药理学和基因操作（CRISPR）为了阐明控制 MEP TZ 髓鞘化神经胶质平铺的细胞和分子机制，我们在目标 2 中进行了研究。将确定我们在目标 1 中描述的相同机制是否也介导少突胶质细胞之间的平铺发育中的脊髓中的祖细胞 (OPC) 更好地了解、诊断和治疗许多细胞。 CNS和PNS的退行性疾病，我们需要了解细胞和分子机制介导神经胶质-神经胶质相互作用和斑马鱼提供了直接观察和平铺的独特机会。操纵细胞群以深入了解神经胶质细胞在正常生理条件下如何相互作用，以及如果那些最终导致神经胶质平铺的相互作用在疾病中受到干扰。