Schwann Cell Reprogramming after Nerve Injury

神经损伤后雪旺细胞重编程

基本信息

批准号：
10735147
负责人：
Rajeshwar B Awatramani
金额：
$ 54.18万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735147
关键词：
Acceleration Action Potentials Aging Automobile Driving Axon Binding Cell Reprogramming Central Nervous System Chronic Communicable Diseases Complex Denervation Deubiquitination Development Diabetic Neuropathies Disease Distal Enhancers Ensure Gene Activation Gene Expression Genes Genetic Diseases Genetic Transcription Goals Histones Homeostasis Impairment Inflammation Injury Knock-out Laboratories Mediating Metabolic Methylation Modeling Mus Myelin Natural regeneration Nerve Nerve Regeneration Nerve compression syndrome Nervous System Neural Crest PRC1 Protein Pathway interactions Peripheral Nerves Peripheral Nervous System Peripheral nerve injury Play Polycomb Process Proteins Regulation Repression Resources Role SHH gene Schwann Cells Signal Transduction Techniques Testing Therapeutic Time Transcription Factor AP-1 Trauma Ubiquitination Work axon regeneration cell type chemotherapy epigenomics gene network histone modification insight jun Oncogene myelination nerve damage nerve injury nerve repair nervous system development nervous system disorder neurodevelopment neuronal survival neurotrophic factor novel peripheral nerve regeneration prevent programs regeneration potential regenerative remyelination repaired response response to injury severe injury smoothened signaling pathway stem cell niche tool transcription factor ubiquitin isopeptidase

项目摘要

Abstract Myelination of axons in the nervous system is critical for not only conduction of action potentials, but also for providing tropic support to ensure long term survival of neurons in both the central and peripheral nervous systems. Myelin disorders are a major cause of neurological disease, and can be caused by genetic disorders, infectious disease, and inflammation. The peripheral nervous system has substantial plasticity in being able to regenerate after nerve injury, and critical transcription factors and their target gene networks have begun to be elucidated. Schwann cell reprogramming to a new differentiated state is a critical and rate limiting factor in peripheral nerve regeneration, particularly when regeneration is impaired as a function of aging/chronic denervation. Therefore, understanding the pathways that control gene expression reprogramming will provide insight into means by which remyelination after nerve injury can be accelerated. The long term objective of our laboratory is to elucidate an integrated mechanism of Schwann cell reprogramming after nerve injury based on critical transcriptional and epigenomic switches. We have found that many critical injury genes are associated with polycomb-associated histone modifications (H3K27me3 and H2AK119ub) prior to injury, and this proposal focuses on testing how reversal of the polycomb pathway is required for Schwann cell responses to peripheral nerve injury. We have also found an expected role of polycomb eraser proteins in myelin homeostasis. Using a variety of techniques established in our laboratory, we will test for the first time the involvement of modulating PRC1 pathway in nerve injury responses. In addition, our work has highlighted mechanisms by which Sonic Hedgehog is activated in repair Schwann cells, and we will employ novel mouse resources to elucidate the mechanisms and role of Sonic Hedgehog signaling in injured peripheral nerve.

抽象的神经系统中轴突的髓鞘化不仅对于行动的传导至关重要潜力，而且还提供热带支持，以确保神经元的长期存活中枢和周围神经系统。髓鞘质紊乱是导致神经系统疾病，可由遗传性疾病、传染病和炎。周围神经系统具有很大的可塑性，能够神经损伤后的再生，关键转录因子及其靶基因网络已经开始得到阐明。雪旺细胞重编程至新的分化状态是周围神经再生的关键和速率限制因素，特别是再生时由于衰老/慢性去神经支配而受损。因此，了解路径控制基因表达重编程将提供对控制基因表达重编程的深入了解可加速神经损伤后的髓鞘再生。我们实验室的长期目标是阐明一个综合机制基于关键转录和神经损伤后雪旺细胞重编程表观基因组开关。我们发现许多严重损伤基因与损伤前多梳相关的组蛋白修饰（H3K27me3 和 H2AK119ub），以及该提案的重点是测试如何逆转多梳途径雪旺细胞对周围神经损伤的反应。我们还发现了预期的角色髓磷脂稳态中的多梳擦除蛋白。使用各种已建立的技术我们的实验室，我们将首次测试调节 PRC1 通路的参与神经损伤反应。此外，我们的工作还强调了索尼克的机制 Hedgehog 在修复施万细胞中被激活，我们将利用新颖的小鼠资源来阐明 Sonic Hedgehog 信号传导在受损周围神经中的机制和作用。