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Clonal analysis of gliogenesis in the cerebral cortex

大脑皮层胶质生成的克隆分析

基本信息

批准号：
10260078
负责人：
Hooman Troy Ghashghaei
金额：
$ 53.2万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10260078
关键词：
Address Alleles Alzheimer&apos s Disease Area Behavior Bioinformatics Biological Biology Brain Brain Neoplasms Candidate Disease Gene Cell Cycle Cell Lineage Cells Cerebral cortex Color Computer Analysis Data Development Disease Dorsal Dose Embryo Epidermal Growth Factor Receptor Equilibrium Event Experimental Models Gene Expression Generations Genes Genetic Genotype Glioma Gliosis Goals Hippocampal Formation Hippocampus (Brain)Homeostasis Individual Injury Ions Knowledge Label Lead Life Maps Methodology Methods Mitotic Recombination Modeling Mosaicism Multiple Sclerosis Mus Neocortex Neurodevelopmental Disorder Neuroglia Neurons Pathologic Pattern Plant Roots Population Population Sizes Production Prosencephalon Proteins Regulation Research Research Proposals Resolution Role Siblings Spinal cord injury Stroke Structure Structure-Activity Relationship Techniques Testing Time Trees analytical method base biological systems cell behavior cell growth cell type dosage falls glial cell development gliogenesis improved in vivo mathematical model multimodality nerve stem cell nervous system disorder neurogenesis new technology novel olfactory bulb postnatal postnatal development progenitor regeneration potential regenerative approach regional difference response response to brain injury response to injury single-cell RNA sequencing stem cell expansion tissue regeneration

项目摘要

The cerebral cortex critically relies on balanced production of neurons and glia during embryonic and early postnatal development. Recently developed clonal lineage analysis has revealed the behavior of neural stem cells (NSCs) giving rise to neurons in the cerebral cortex with unprecedented single-cell resolution. However, the formation of glia by NSCs remains unclear and has yet to be systematically investigated using these new technologies. Gliogenesis is critical for proper neuronal functions and when disrupted, it can result in various neurological diseases. Reconstructing how glia are generated from individual NSCs and organized in the cortex during development is essential to understand the structure-function relationships and how they can be modulated by clone-specific factors. We have established a genetically-based single-cell lineage tracing technique utilizing MADM (Mosaic Analysis with Double Markers) mice to label NSCs in the developing cortex and begin to address this knowledge gap. Using this method we have found two distinct populations of glia that occupy different territories of the cortex and its related structure the hippocampal formation. The goal of the proposed research is to reconstruct, quantify, and mathematically model the behavior of individually labeled NSCs in vivo. We will use the power of this labeling method to also screen for gene expression of glial clones at single cell resolution, which all together will help us decipher the general principles organizing glial clones in the cortex, and define how clonal siblings interact with each other. We will test the role of some of the identified genes in generation of glial clones in the cortex, which will further help define the biological system underlying principles of gliogenesis. Successful completion of our study will result in a comprehensive map of single NSCs and their glial progeny in various cortical regions. Our approach will also establish a platform for detailed quantitative and computational analysis of gliogenesis, glial diversity, and their potential for regenerative approaches in the cortex. Potential for Broader Impact Our approaches to understand how important constituents of the brain, the glial cells, develop have wide implications. Disruption of glial development is the root of a range of pathological conditions in the brain. Therefore, understanding the basic principles and cellular mechanisms that control gliogenesis is critical to appreciate not only how healthy development may be controlled by systematic production of glial cells, but also how abnormalities in gliogenesis may lead to devastating neurodevelopmental disorders and brain tumors.

大脑皮层在胚胎和早期非常依赖于神经元和神经胶质细胞的平衡产生。后天发育。最近发展起来的克隆谱系分析揭示了神经干细胞的行为细胞(NSCs)以前所未有的单细胞分辨率在大脑皮层中产生神经元。然而，神经干细胞形成神经胶质细胞的机制尚不清楚，尚未利用这些新技术进行系统研究。技术。胶质形成对正常的神经元功能至关重要，当受到干扰时，它可以导致各种神经系统疾病。重建神经胶质细胞是如何从单个神经干细胞产生并在发育过程中的皮质对于理解结构-功能关系以及它们是如何受克隆特有因子的调节。我们已经建立了一种基于基因的单细胞谱系追踪利用MADM小鼠标记发育中皮质神经干细胞的技术并开始解决这一知识鸿沟。使用这种方法，我们发现了两种不同的胶质细胞群体占据不同区域的皮质及其相关结构，即海马体结构。的目标是建议的研究是重建、量化和数学建模个别标记的行为体内的神经干细胞。我们将利用这种标记方法的力量来筛选神经胶质克隆的基因表达在单细胞分辨率下，所有这些都将帮助我们破译组织神经胶质克隆的一般原理大脑皮层，并定义克隆兄弟姐妹如何相互作用。我们将测试一些已确定的角色基因在皮质神经胶质克隆的生成中的作用，这将进一步帮助定义潜在的生物系统神经胶质发生的原理。成功完成我们的研究将产生一张关于单个NSC的全面地图以及它们在不同皮质区域的神经胶质后代。我们的方法还将建立一个详细的平台神经胶质发生、神经胶质多样性及其再生潜能的定量和计算分析进入大脑皮层。潜在的更广泛的影响我们了解大脑的重要组成部分--神经胶质细胞如何发育的方法很广泛。这意味着什么。神经胶质发育障碍是大脑中一系列病理性疾病的根源。因此，了解控制胶质形成的基本原理和细胞机制对于不仅要了解胶质细胞的系统性生产如何控制健康的发育，而且要了解胶质形成的异常如何导致毁灭性的神经发育障碍和脑瘤。