The Role of ESCRTs in Regulating Nervous System Function

ESRT 在调节神经系统功能中的作用

• 批准号: 10056232
• 负责人: Scott Michael Wilson
• 金额: $ 32.89万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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/10056232
• 关键词: Affect; Alleles; Animal Model; Axon; Binding; Biochemical; Biological; Biological Models; Biology; Cell Culture Techniques; Cell Differentiation process; Cell Maturation; Cell Proliferation; Cell Surface Receptors; Cell physiology; Cells; Charcot-Marie-Tooth Disease; Complex; Critical Pathways; Cyclic AMP; Data; Defect; Demyelinating Diseases; Demyelinations; Development; Disease; EGFR gene; ERBB2 gene; Endosomes; Foundations; Functional disorder; Gene Expression; Genes; Goals; HGS gene; Impairment; Inherited; Instruction; Laboratories; Leukoencephalopathy; Link; Motor; Mus; Mutant Strains Mice; Myelin; Myelin Sheath; NRG1 gene; Nervous System Physiology; Neuregulin 1; Neuropathy; Pain; Paralysed; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Positioning Attribute; Process; Production; Proteins; RNA Sequence Analysis; Radial; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Regulatory Pathway; Rodent Model; Role; Route; Schwann Cells; Sensory; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Testing; United States; cell type; dimer; disease-causing mutation; dysmyelination; experimental study; extracellular; functional restoration; gene induction; genetic analysis; hepatocyte growth factor-regulated tyrosine kinase substrate; improved; insight; migration; mouse model; myelination; nervous system disorder; novel; protein complex; receptor; receptor function; receptor internalization; repaired; sciatic nerve; therapeutic target; therapy development; trafficking; transcriptome sequencing; treatment strategy

Peripheral neuropathies affect more than 20 million people in the United States. Patients with peripheral neuropathies suffer from debilitating motor and sensory deficits that can cause severe pain and paralysis. Many forms of inherited peripheral neuropathies impair Schwann cell function and result in abnormal myelin production or demyelination, which is thought to be the underlying cause of the motor and sensory deficits. Schwann cells intimately associate with axons to organize peripheral nerves during development and to insulate axons with myelin. The NRG1/ERBB signaling pathway allows for Schwann cells and axons to communicate with each other and provides essential instructions that regulate Schwann cell proliferation, migration and myelination. Modulation of the NRG1/ERBB signaling pathway can restore function to several rodent models of Charcot-Marie-Tooth disease (CMT). Therefore, identifying the mechanisms that control NRG1/ERBB signaling has important implications for the treatment of peripheral neuropathies. Our data from mice and cell culture experiments indicate that the endosome is a critical regulator of ERBB2/3 function during myelination. To investigate the endosomal pathways controlling ERBB2/3 signaling, we have developed mouse models that impair endosomal sorting of internalized cell surface receptors. We have focused on hepatocyte growth factor regulated tyrosine kinase substrate (HGS), which directs the sorting of internalized receptors through the endosome. HGS expression is diminished in two different mouse models of CMT, implicating defective endosomal sorting as a cause for demyelinating neuropathies. Our data now indicate that loss of HGS in Schwann cells replicates many features of inherited peripheral nerve disorders, including motor and sensory deficits and dysmyelination of sciatic nerves. Impairing endosomal function by deleting the Hgs gene specifically in Schwann cells also showed that ERBB2/3 receptor signaling is dependent upon endosomal sorting to activate its downstream signaling pathways. In addition, we have identified a novel endosomal protein complex in Schwann cells that occurs during myelination. To test the hypothesis that endosomal sorting regulates ERBB2/3 function during myelination, Aim 1 will determine the role of endosomal sorting in Schwann cells for the development and function of peripheral nerves, and Aim 2 will determine how endocytic trafficking controls the sorting and signaling of the ERBB2/3 receptors in Schwann cells. To investigate the mechanism regulating ERBB2/3 function in Schwann cells, Aim 3 will determine which HGS interacting protein complexes are required for ERBB2/3 sorting and signaling in Schwann cells. The completion of this proposal is expected to provide novel insights on the endosomal biology of Schwann cells and further our understanding of how endosomal sorting controls ERBB receptor signaling during myelination. Our long-range goals are to determine the regulatory pathways that control endosomal function in Schwann cells in order to identify targets for the treatment of demyelinating diseases such as CMT.

周围神经病变影响美国超过2000万人。周围型 神经病遭受使人衰弱的运动和感觉缺陷，其可引起严重的疼痛和瘫痪。 许多形式的遗传性周围神经病损害雪旺细胞功能，导致髓鞘异常 这被认为是运动和感觉缺陷的根本原因。 雪旺细胞与轴突密切相关，在发育过程中组织周围神经， 用髓磷脂隔离轴突。NRG 1/ERBB信号通路允许许旺细胞和轴突 它们相互沟通并提供调节许旺细胞增殖的基本指令， 迁移和髓鞘形成。调节NRG 1/ERBB信号通路可以恢复几个神经元的功能。 Charcot-Marie-Tooth病（CMT）的啮齿动物模型。因此，确定控制 NRG 1/ERBB信号传导对周围神经病的治疗具有重要意义。我们的数据来自 小鼠和细胞培养实验表明，内体是ERBB 2/3功能的关键调节剂， 髓鞘形成为了研究控制ERBB 2/3信号传导的内体途径，我们培育了小鼠 模型损害内化的细胞表面受体的内体分选。我们专注于肝细胞 生长因子调节的酪氨酸激酶底物（HGS），指导内化受体的分选 通过内体。在两种不同的CMT小鼠模型中，HGS表达减少，提示 内体分选缺陷是导致脱髓鞘性神经病的原因。我们的数据显示， 雪旺氏细胞中的HGS复制了遗传性周围神经障碍的许多特征，包括运动和神经功能障碍。 感觉缺陷和坐骨神经髓鞘形成障碍。通过删除Hgs基因损害内体功能 特别是在Schwann细胞中的研究也表明ERBB 2/3受体信号传导依赖于内体 排序以激活其下游信号通路。此外，我们还发现了一种新的内体蛋白， 在髓鞘形成过程中发生的雪旺氏细胞中的蛋白质复合物。为了验证内体分选 调节ERBB 2/3在髓鞘形成过程中的功能，Aim 1将确定内体分选在雪旺氏细胞中的作用。 细胞用于外周神经的发育和功能，Aim 2将确定内吞运输如何进行 控制雪旺细胞中ERBB 2/3受体的分选和信号传导。为了研究其机制 调节ERBB 2/3在雪旺细胞中的功能，目的3将确定哪些HGS相互作用蛋白复合物 是雪旺细胞中ERBB 2/3分选和信号传导所必需的。预计这项提案将于 为雪旺细胞的内体生物学提供新的见解， 内体分选控制髓鞘形成过程中的ERBB受体信号传导。我们的长期目标是确定 控制雪旺细胞内体功能的调节途径，以确定 治疗脱髓鞘疾病如CMT。