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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：
10318602
负责人：
Scott Michael Wilson
金额：
$ 32.91万
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/10318602
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 Persons 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，周围神经病变影响着超过2000万人。外周患者