Aging dependent transformation of oligodendrocyte precursor cells

少突胶质细胞前体细胞的衰老依赖性转化

基本信息

批准号：
10390424
负责人：
DWIGHT E BERGLES
金额：
$ 33.57万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10390424
关键词：
Ablation Address Age Aging Amyotrophic Lateral Sclerosis Animals Antigen Presentation Pathway Antigens Astrocytes Autophagocytosis Back Behavior Brain Brain Diseases Brain region CSPG4 gene Calcium Calcium Signaling Cell Aging Cell division Cell physiology Cells Characteristics Chondroitin Sulfate A Cicatrix Complex Computational Biology DNA Repair Data Set Development Disease Environment Exhibits Exposure to Expression Profiling Extracellular Matrix Filopodia Generations Genetic Transcription Growth Factor Heterogeneity Homeostasis Image Immune Inflammation Inflammatory Injury Ions Knockout Mice Knowledge Lead Learning Life MHC Class I Genes MHC antigen Metabolic Methodology Microglia Molecular Molecular Biology Monitor Multiple Sclerosis Mus Myelin Myelin Sheath Natural regeneration Nervous system structure Neuroglia Neurons Neurotransmitters Norepinephrine Oligodendroglia Organ Pattern Phenotype Physiological Physiology Play Population Population Heterogeneity Process Production Property Proteoglycan Radial Rejuvenation Role Signal Transduction Site Synapses Testing Therapeutic Time Tissues Transgenic Mice Traumatic Brain Injury age effect age related aging brain cell behavior cell motility cell type conditional knockout cytokine density design environmental change experience gray matter imaging study in vivo in vivo imaging innovation insight migration millisecond motor learning myelination neural circuit neurotransmission novel novel strategies oligodendrocyte precursor oligodendrocyte progenitor precursor cell preservation progenitor regeneration potential repaired response self renewing cell senescence single-cell RNA sequencing stem tool two-photon white matter young adult

项目摘要

Summary: To sustain neural signaling and enable plasticity throughout life, the nervous system relies on homeostatic interactions with a diverse population of glial cells, which create and modify the extracellular matrix, remove ions and neurotransmitters, provide metabolic support and promote functional reorganization of circuits in response to changing patterns of activity. Although most studies of glial cells have focused on the three main classes of glia – astrocytes, oligodendrocytes and microglia – the mammalian brain also contains an abundant, highly dynamic population of glial progenitors termed oligodendrocyte precursor cells (OPCs or NG2 glia). These lineage restricted progenitors play crucial roles in generating oligodendrocytes to enable production of new myelin sheaths during motor learning and replacement of myelin destroyed through disease, such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). OPCs remain widely distributed in gray and white matter throughout life, but exhibit profound changes in behavior with aging, including reduced proliferation and differentiation. Emerging evidence suggests that OPCs do more than serve as progenitors for oligodendrocytes, as they are found in regions where there is no myelin, and like microglia, OPCs migrate to sites of injury and contribute to scar formation, features unrelated to their role in oligodendrogenesis and myelin repair. OPCs share many other features with microglia – they are present at a similar density, maintain a grid-like distribution, possess ramified, radially-oriented processes and are highly dynamic, continuously exploring their surrounding environment with motile filopodia. Moreover, recent evidence indicates that OPCs can transform into inflammatory OPCs (iOPCs) that engulf and present exogenous antigens through MHC class I and II when exposed to inflammatory cytokines, suggesting that they may modulate tissue inflammation. While microglia and astrocytes are known to undergo phenotypic changes in response to inflammation that profoundly influence the aging brain, much less is known about the role of OPCs in this context, despite their persistence in brain circuits. In part, this lack of knowledge stems from the limited molecular and physiological interrogation of OPCs that has been completed in vivo. OPCs are underrepresented in available single cell RNA-seq datasets and there have been no studies specifically designed to define how changes in their properties with aging are influenced by their prior behavior. We will leverage a diverse array of methodologies and our combined expertise in physiology, molecular and computational biology to define the causes and consequences of age-dependent changes in these ubiquitous glial cells. The new insight provided by these studies may lead to a deeper understanding of the homeostatic roles performed by these glial cells, and reveal new approaches for rejuvenating their regenerative potential to sustain brain function throughout life.

概括：为了维持神经信号传导和使可塑性一生，神经系统依赖于稳态与胶质细胞的潜水员种群的相互作用，这些细胞产生和修改细胞外基质，去除离子和神经递质，提供代谢支持并促进电路中电路的功能重组对不断变化的活动模式的响应。尽管大多数对神经胶质细胞的研究都集中在这三个主要胶质细胞类别 - 星形胶质细胞，少突胶质细胞和小胶质细胞 - 哺乳动物大脑还包含丰富的，神经胶质祖细胞的高度动态种群称为少突胶质细胞前体细胞（OPC或NG2 Glia）。这些谱系受限制的祖细胞在产生少突胶质细胞中起着至关重要的作用运动学习期间的新髓鞘和髓磷脂被疾病破坏的髓鞘，例如多发性硬化症（MS）和肌萎缩性侧面硬化症（ALS）。 OPC仍然广泛分布在灰色和一生中的白质，但随着衰老的行为发生了深刻的变化，包括减少增殖和分化。新兴的证据表明，OPC的作用不仅仅是作为祖细胞少突胶质细胞，因为它们在没有髓磷脂的区域发现，并且像小胶质细胞一样，OPC迁移到损伤部位并导致疤痕形成，特征与它们在寡聚发生和髓鞘修复。 OPC与小胶质细胞共享许多其他功能 - 它们以相似的密度存在，保持类似网格的分布，潜在的分布，彻底面向的过程，高度动态，连续通过动动丝状探索周围环境。此外，最近的证据表明OPC 可以转变为吞噬并通过MHC吞噬外源抗原的炎症OPC（IOPC） I级和II暴露于炎性细胞因子时，表明它们可能调节组织注射。虽然已知小胶质细胞和星形胶质细胞会因炎症而经历表型变化，但深刻影响大脑衰老的大脑，对OPC在这种情况下的作用知之甚少，dospite他们脑电路的持久性。在某种程度上，这种缺乏有限分子和生理学的知识植物对体内完成的OPC的询问。 OPC在可用的单元中的代表性不足 RNA-seq数据集，并且没有专门设计的研究来定义其如何变化具有衰老的特性受其先前行为的影响。我们将利用一系列潜水员的方法以及我们在生理学，分子和计算生物学方面的综合专业知识，以定义原因和这些无处不在的神经胶质细胞中年龄依赖性变化的后果。这些提供的新见解研究可能会导致对这些神经胶质细胞执行的稳态角色的更深入了解，并揭示新方法恢复了其再生潜力，以维持一生的脑功能。