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.

抽象的 在脊椎动物周围神经系统中，schwann细胞（SC）使髓磷脂可绝缘大轴突和 允许快速传导神经冲动。髓鞘的SC具有天生的脱髓鞘和脱髓力的能力 转变为修复SC，从而促进创伤性损伤后的轴突再生和透明度。 脱髓鞘也可以在病理上发生，并且没有有效的治疗方法来促进或增强 受伤或疾病后的再髓。发育过程中的髓鞘化是通过激活几个SC引发的 膜相关蛋白，并要求转录因子KROX20在细胞核中。然而， 我们对髓鞘形式信号在发育过程中如何从膜转移到细胞核，并且 关于髓磷脂维持和透明度所需的信号甚至更少。 yap/taz是寄生虫 具有不同细胞功能的转录共激活蛋白，称为细胞的有效启动子 增殖。它们的活性受核细胞质穿梭的调节：当核时，它们是转录的 积极的。我们最近表明，在SCS中，YAP/TAZ是核的，需要KROX20表达，髓磷脂 形成和维护，表明YAP/TAZ穿梭信号从膜到核调节 髓鞘。这些发现使我们假设yap/taz是多个信号通路的联系 这导致KROX20和髓磷脂基因的转录激活，从而调节发育 髓鞘，髓鞘维持，脱髓鞘和透明度。为了检验我们的假设，我们提出了 以下目的：1）确定YAP/TAZ是否介导脱髓鞘和再生； 2）识别上游 在髓鞘形成和维护中，YAP/TAZ的调节剂； 3）确定YAP/TAZ如何调节 KROX20和髓磷脂基因的转录。我们将使用独特而常规的体外和体内技术， 包括多个可诱导的转基因小鼠和核糖翻译体分析。拟议的研究 应该显着增强我们对SC形成，维护和修复周围髓磷脂的理解。这是 还可能提供重要的新见解，以防止脱髓鞘或促进稳健的再生性 在周围神经疾病中。