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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要