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: 10531223
• 负责人: Scott Michael Wilson
• 金额: $ 32.92万
• 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/10531223
• 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; Central Nervous System; Charcot-Marie-Tooth Disease; Communication; 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; Nervous System Physiology; Neuregulin 1; Neuropathy; Pain; Paralysed; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Persons; Positioning Attribute; Process; Production; Proliferating; 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; 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.

在美国，周围神经病会影响超过2000万人。外围患者 神经病患有令人衰弱的运动和感觉缺陷，可能导致严重的疼痛和麻痹。 多种形式的遗传性周围神经病损害了施旺细胞功能，并导致异常髓磷脂 产生或脱髓鞘，被认为是运动和感觉缺陷的根本原因。 Schwann细胞与轴突紧密相关，以在发育过程中组织周围神经 用髓磷脂将轴突隔离。 NRG1/ERBB信号通路允许Schwann细胞和轴突 彼此交流，并提供调节Schwann细胞增殖的基本指令， 迁移和髓鞘。 NRG1/ERBB信号通路的调节可以将功能恢复到几个 啮齿动物 - 玛丽齿病（CMT）的啮齿动物模型。因此，确定控制的机制 NRG1/ERBB信号传导对外周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ERBB2/3功能的关键调节剂 髓鞘。为了研究控制ERBB2/3信号的内体途径，我们已经开发了小鼠 损害内体性细胞表面受体的内体分选的模型。我们专注于肝细胞 生长因子调节的酪氨酸激酶底物（HGS）指导内部化受体的分类 通过内体。 HGS表达在CMT的两个不同的鼠标模型中减少，这意味着 内体分类有缺陷，是神经病脱髓鞘的原因。我们的数据现在表明丢失 Schwann细胞中的HGS复制了遗传性周围神经疾病的许多特征，包括运动和 坐骨神经的感觉缺陷和荧光差异。通过删除HGS基因来损害内体功能 特别是在Schwann细胞中还表明，ERBB2/3受体信号取决于内体 排序以激活其下游信号通路。此外，我们已经确定了一种新型内体 在髓鞘化过程中发生的雪旺细胞中的蛋白质复合物。测试内体分类的假设 调节髓鞘中的ERBB2/3功能，AIM 1将确定内体分类在Schwann中的作用 细胞开发和功能的周围神经，AIM 2将决定内吞运输的方式 控制Schwann细胞中ERBB2/3受体的分类和信号传导。调查机制 调节Schwann细胞中的ERBB2/3功能，AIM 3将确定哪些HGS相互作用的蛋白质复合物 schwann细胞中的ERBB2/3分类和信号传导所需。预计该提案的完成 提供有关Schwann细胞内体生物学的新见解，并进一步了解我们如何理解 内体分选控制髓鞘过程中ERBB受体信号传导。我们的远程目标是确定 控制Schwann细胞中内体功能的调节途径，以识别 脱髓鞘疾病（例如CMT）的治疗。