Functional role of satellite glial cells in axon regeneration

卫星胶质细胞在轴突再生中的功能作用

• 批准号: 9913648
• 负责人: Valeria Cavalli
• 金额: $ 43.09万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913648
• 关键词: Adult; Affect; Afferent Neurons; Attention; Axon; Biological Models; Biology; Brain; Candidate Disease Gene; Cell Differentiation process; Cells; Coculture Techniques; Communication; Complex; Cues; Data; Embryo; Enzymes; Ethers; Fatty Acids; Fatty-acid synthase; Gene Expression; Gene Expression Profile; Generations; Genes; Genetic; Genetic Transcription; Goals; Human; Immunofluorescence Immunologic; Impairment; In Situ Hybridization; Inflammation; Injury; Link; Lipids; Molecular; Molecular Profiling; Mus; Natural regeneration; Nerve; Nerve Regeneration; Neuraxis; Neuroglia; Neurons; Nociception; Pain; Palmitic Acids; Pathologic; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Phospholipids; Physiology; Plasmalogens; Play; Process; Property; Recovery of Function; Regenerative response; Research; Research Proposals; Role; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Speed; Spinal Ganglia; Structure; System; Testing; Time; axon growth; axon injury; axon regeneration; base; central nervous system injury; chemotherapy; chronic pain; experimental study; functional outcomes; human model; in vivo; injured; innovation; lipid metabolism; live cell imaging; mature animal; mouse model; nerve injury; nervous system disorder; neuronal cell body; novel marker; novel therapeutics; painful neuropathy; peripheral nerve regeneration; regenerative; repaired; response; satellite cell; sciatic nerve; single cell sequencing; single-cell RNA sequencing; virtual

ABSTRACT Identifying strategies to increase the speed and extent of axon regeneration is important for central nervous system injuries, where axon regeneration usually fails. In contrast, peripheral sensory neurons with cell body in dorsal root ganglia can switch to a regenerative state after axon injury to promote regeneration and functional recovery. Studies on the effect of nerve injury on sensory neurons have revealed multiple neuronal intrinsic signaling mechanisms that promote axon regeneration. However, virtually nothing is known about the contribution of satellite glial cells (SGC) that envelop the neuronal soma in the nerve repair process. A better understanding of the role of SGC is important and highly significant. In this proposal, we outline experiments to uncover the transcriptional changes elicited in SGC following nerve injury and establish the mechanisms by which SGC contribute to sensory neurons' regenerative abilities. SGC form a sheath that completely surround sensory neurons, resulting in each neuron together with its satellite cell sheath constituting a discrete functional unit. We know that SGCs are altered structurally and functionally under pathological conditions associated with chronic pain and communication between sensory neurons and SGC plays a critical role in nociception. Based on our preliminary studies, we have now reason to believe that SGC play a previously unrecognized role in peripheral nerve regeneration. We will reveal the transcriptional profile of SGC in response to nerve injury using single cell sequencing approaches and determine if SGC subtypes exist. We will use human DRG to determine the transcriptional profile of human SGC and their role in axon growth using co-culture approaches. These experiments will allow us to reveal if findings made in the mouse model system are predictive of the physiology of human neurons. We have also established a neuron-SGC co-culture system that allows us to visualize and quantify how SGC envelop sensory neuron soma and determine SGC's role in sensory axon growth and regeneration. Finally, we will build on our findings that SGC upregulate genes related to lipid metabolism after injury to test if de novo fatty acid synthesis in SGC affect gene expression and axon regeneration following nerve injury. We will focus on Fatty acid synthase (Fasn), the key enzyme in de novo fatty acid synthesis, which we found is upregulated in SGC after nerve injury. Fasn synthesizes palmitic acid, which is the substrate for the synthesis of more complex fatty acids, such as ether linked phospholipids (including plasmalogens). Plasmalogens are enriched in the brain and play important roles in cell signaling and differentiation and are implicated in neurological disorders. We will use genetic and lipidomics approaches to determine how lipid metabolism in SGC contribute to the axon regeneration process. Through these experiments, we will uncover the contribution of SGC and plasmalogens to nerve injury and their functional role in axon regeneration.

抽象的 确定提高轴突再生速度和程度的策略对于中枢神经很重要 轴突再生通常失败的系统伤害。相反，具有细胞体的周围感觉神经元 在背根中，神经节可以在轴突受伤后切换到再生状态，以促进再生和 功能恢复。关于神经损伤对感觉神经元影响的研究表明多个神经元 促进轴突再生的固有信号传导机制。但是，几乎什么都没知道 卫星神经胶质细胞（SGC）在神经修复过程中包裹神经元体的贡献。更好 了解SGC的作用是重要且非常重要的。在此提案中，我们概述了实验 发现神经损伤后SGC引起的转录变化并建立机制 SGC促进了感觉神经元的再生能力。 SGC形成一个完全围绕感官神经元的鞘，导致每个神经元与 它的卫星细胞鞘构成离散功能单元。我们知道SGC在结构上发生了变化，并且 在与慢性疼痛和感觉之间沟通相关的病理状况下的功能上 神经元和SGC在伤害受伤中起着至关重要的作用。根据我们的初步研究，我们现在有理性 相信SGC在周围神经再生中起着以前无法识别的作用。我们将揭示 SGC使用单细胞测序方法对神经损伤的转录谱，并 确定是否存在SGC亚型。我们将使用人类DRG来确定人类的转录特征 SGC及其在轴突生长中使用共培养方法的作用。这些实验将使我们能够揭示 小鼠模型系统中提出的发现可以预测人类神经元的生理。我们也有 建立了一个神经元SGC共培养系统，该系统使我们能够可视化和量化SGC的信封 感觉神经元体体并确定SGC在感觉轴突生长和再生中的作用。最后，我们会的 基于我们的发现，即SGC在受伤后上调与脂质代谢相关的基因以测试是否从头脂肪 SGC中的酸合成会影响神经损伤后基因表达和轴突再生。我们将重点关注 脂肪酸合酶（FASN），即从头脂肪酸合成中的关键酶，我们发现它已上调 神经损伤后的SGC。 FASN合成棕榈酸，这是合成更多的底物 复杂的脂肪酸，例如醚链磷脂（包括浆元）。浆元富集 在大脑中并在细胞信号传导和分化中起重要作用，并与神经学有关 疾病。我们将使用遗传学和脂肪组学方法来确定SGC中的脂质代谢如何 有助于轴突再生过程。通过这些实验，我们将发现 SGC和血浆元素可致神经损伤及其在轴突再生中的功能作用。