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：
10208074
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/10208074
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并在整个生命过程中实现可塑性，神经系统依赖于稳态与不同的神经胶质细胞群相互作用，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回路的功能重组尽管大多数神经胶质细胞的研究都集中在三个主要方面。胶质细胞类别——星形胶质细胞、少突胶质细胞和小胶质细胞——哺乳动物大脑还含有丰富的、高度动态的神经胶质祖细胞群，称为少突胶质细胞前体细胞（OPC 或 NG2 神经胶质细胞）。这些谱系限制性祖细胞在生成少突胶质细胞以实现运动学习过程中产生新的髓鞘，并替换因疾病而破坏的髓鞘，例如多发性硬化症 (MS) 和肌萎缩侧索硬化症 (ALS) 仍然广泛分布在灰色和灰色地带。在整个物质生命周期中呈白色，但随着衰老而表现出深刻的行为变化，包括减少新出现的证据表明，OPC 的作用不仅仅是作为祖细胞。少突胶质细胞，因为它们存在于没有髓磷脂的区域，并且像小胶质细胞一样，OPC 会迁移到损伤部位并有助于疤痕形成，其特征与其在少突胶质细胞发生中的作用无关，髓磷脂修复与小胶质细胞有许多其他共同特征——它们的密度相似。网格状分布，具有分叉的、径向的过程，并且是高度动态的、连续的此外，最近的证据表明 OPCs 可以用活动的丝状伪足探索周围环境。可以转化为炎性 OPC (iOPC)，通过 MHC 吞噬并呈递外源抗原当暴露于炎症细胞因子时，I 类和 II 类，表明它们可以调节组织炎症。虽然已知小胶质细胞和星形胶质细胞会因炎症反应而发生表型变化，尽管OPCs对大脑老化有着深远的影响，但人们对OPCs在这方面的作用知之甚少。这种知识的缺乏部分源于有限的分子和生理学知识。已在体内完成的 OPC 询问在可用的单细胞中代表性不足。 RNA-seq 数据集，并且还没有专门设计来定义其变化如何的研究老化特性受到其先前行为的影响，我们将利用多种方法。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来确定原因和这些普遍存在的神经胶质细胞的年龄依赖性变化的后果由这些提供了新的见解。研究可能会导致人们更深入地了解这些神经胶质细胞所发挥的稳态作用，并揭示恢复其再生潜力以维持终生大脑功能的新方法。