The Role of ESCRTs in Regulating Nervous System Function

ESRT 在调节神经系统功能中的作用

基本信息

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
项目类别：
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

项目摘要

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，周围神经病影响着超过 2000 万人。外周病患者神经病患者的运动和感觉缺陷会导致严重的疼痛和瘫痪。许多形式的遗传性周围神经病都会损害雪旺细胞功能并导致髓磷脂异常产生或脱髓鞘，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并用髓磷脂隔离轴突。 NRG1/ERBB 信号通路允许雪旺细胞和轴突相互沟通并提供调节雪旺细胞增殖的基本指令，迁移和髓鞘形成。 NRG1/ERBB 信号通路的调节可以恢复多种功能腓骨肌萎缩症 (CMT) 啮齿动物模型。因此，确定控制机制 NRG1/ERBB 信号传导对于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 ERBB2/3 功能的关键调节因子髓鞘形成。为了研究控制 ERBB2/3 信号传导的内体途径，我们开发了小鼠损害内化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)，指导内化受体的分类通过内体。 HGS 表达在两种不同的 CMT 小鼠模型中减少，暗示内体分选缺陷是脱髓鞘神经病的一个原因。我们的数据现在表明，损失雪旺细胞中的 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雪旺细胞中，还表明 ERBB2/3 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雪旺细胞中髓鞘形成过程中发生的蛋白质复合物。检验内体分选的假设在髓鞘形成过程中调节 ERBB2/3 功能，目标 1 将决定雪旺中内体分选的作用细胞对周围神经的发育和功能的影响，目标 2 将决定内吞运输的方式控制雪旺细胞中 ERBB2/3 受体的分类和信号传导。研究机制调节雪旺细胞中的 ERBB2/3 功能，Aim 3 将确定哪些 HGS 相互作用蛋白复合物是雪旺细胞中 ERBB2/3 分选和信号转导所必需的。预计该提案的完成提供关于雪旺细胞内体生物学的新见解，并进一步了解我们如何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。