Hippo Regulation of Peripheral Myelination and Nerve Repair

河马对周围髓鞘形成和神经修复的调节

• 批准号: 10373032
• 负责人: YOUNG-JIN SON
• 金额: $ 34.67万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373032
• 关键词: Ablation; Adult; Affect; Alleles; American; Autoimmune Diabetes; Autoimmune Diseases; Automobile Driving; Axon; Axotomy; Binding; Biological Assay; Cell Nucleus; Cell Proliferation; Cell physiology; Communication; Complex; Cytoplasm; Demyelinating Diseases; Demyelinations; Development; Disease; EGR2 gene; Enhancers; Exclusion; Failure; Gene Expression; Genes; Genetic Enhancer Element; Genetic Transcription; In Vitro; Inflammation; Injury; Investigation; Knowledge; LATS1 gene; Lead; Life; Maintenance; Mediating; Mediator of activation protein; Membrane; Membrane Proteins; Molecular; Motor; Myelin; Myelin Sheath; Natural regeneration; Nerve; Nerve Sheath Tumors; Neural Conduction; Neuregulins; Neurofibromin 2; Neuropathy; Nuclear; Oncoproteins; Pathologic; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Phosphotransferases; Play; Proteins; Regulation; Research; RiboTag; Role; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Stimulus; Techniques; Testing; Time; Transcription Coactivator; Transcriptional Activation; Transcriptional Coactivator with PDZ-Binding Motif; Transgenic Mice; Traumatic Nerve Injury; Traumatic injury; axon regeneration; cell dedifferentiation; chemotherapy; effective therapy; experimental study; gain of function; in vivo; innovation; insight; loss of function; mutant; myelination; nerve damage; nerve injury; nerve repair; novel; novel strategies; nucleocytoplasmic transport; paralogous gene; prevent; programs; promoter; recruit; remyelination; repaired; targeted cancer therapy; therapy development; transcription factor; translatome

Abstract In the vertebrate peripheral nervous system, Schwann cells (SCs) make myelin that insulates large axons and allows rapid conduction of nerve impulses. Myelinating SCs possess the innate ability to demyelinate and transform into repair SCs, which promote axonal regeneration and remyelination after traumatic injury. Demyelination can also occur pathologically, and there are no effective treatments to promote or enhance remyelination after injury or disease. Myelination during development is triggered by activation of several SC membrane-associated proteins, and requires that the transcription factor Krox20 be in the nucleus. However, we know little about how myelination signals move from the membrane to the nucleus during development and even less about the signaling required for myelin maintenance and remyelination. YAP/TAZ are paralogous transcriptional co-activator proteins with diverse cellular functions, known best as potent promoters of cell proliferation. Their activity is regulated by nucleocytoplasmic shuttling: when nuclear, they are transcriptionally active. We recently showed that in SCs, YAP/TAZ are nuclear and required for Krox20 expression, myelin formation and maintenance, suggesting that YAP/TAZ shuttle signals from membrane to nucleus to regulate myelination. These findings lead us to hypothesize that YAP/TAZ are a nexus for multiple signaling pathways that lead to transcriptional activation of Krox20 and myelin genes, and which thereby regulate developmental myelination, myelin maintenance, demyelination and remyelination. To test our hypothesis, we propose the following Aims: 1) Determine if YAP/TAZ mediate demyelination and remyelination; 2) Identify upstream regulators of YAP/TAZ in myelin formation and maintenance; 3) Determine how YAP/TAZ regulate transcription of Krox20 and myelin genes. We will use unique and conventional in vitro and in vivo techniques, including multiple lines of inducible transgenic mice and RiboTag translatome profiling. The proposed study should significantly enhance our understanding of how SCs form, maintain and repair peripheral myelin. It is also likely to provide important new insights into how to prevent demyelination or promote robust remyelination in peripheral nerve diseases.

摘要 在脊椎动物的周围神经系统中，雪旺细胞(SCs)制造髓鞘，隔离大的轴突和 允许神经冲动的快速传导。髓鞘干细胞具有先天的脱髓鞘能力和 转化为修复干细胞，促进创伤后轴突再生和髓鞘再生。 脱髓鞘也可以发生在病理上，没有有效的治疗方法来促进或加强 损伤或疾病后的再髓鞘形成。发育过程中的髓鞘形成是由几个SC的激活触发的 膜相关蛋白，并要求转录因子Krox20位于细胞核内。然而， 我们对髓鞘信号如何在发育和发育过程中从膜转移到细胞核知之甚少。 更不用说髓鞘维持和再髓鞘形成所需的信号。YAP/TAZ是平行的 转录共激活蛋白具有多种细胞功能，最为人所知的是强大的细胞促进剂 扩散。它们的活性受核质穿梭的调节：当它们有核时，它们是转录的 激活。我们最近发现，在干细胞中，YAP/TAZ是核的，Krox20的表达需要髓鞘 YAP/TAZ信号的形成和维持，提示YAP/TAZ信号从膜到核的穿梭调控 髓鞘形成。这些发现使我们假设YAP/TAZ是多个信号通路的纽带 这导致Krox20和髓鞘基因的转录激活，从而调节发育 髓鞘形成、髓鞘维持、脱髓鞘和再髓鞘形成。为了检验我们的假设，我们提出了 以下目标：1)确定YAP/TAZ是否介导脱髓鞘和再髓鞘形成；2)确定上游 YAP/TAZ在髓鞘形成和维持中的调节作用；3)决定YAP/TAZ如何调节 Krox20和髓鞘基因的转录。我们将使用独特和传统的体外和体内技术， 包括多个可诱导转基因小鼠品系和RiboTag翻译组图谱。建议进行的研究 应该会显著提高我们对干细胞如何形成、维持和修复外周髓鞘的理解。它是 也可能为如何预防脱髓鞘或促进强大的髓鞘再生提供重要的新见解 在周围神经疾病方面。