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Polarized Initiation of Varicosity Formation in Central Neuron Mechanosensation

中枢神经元机械感觉中静脉曲张形成的极化起始

基本信息

批准号：
9177341
负责人：
CHEN GU
金额：
$ 34.83万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177341
关键词：
Action Potentials Affect Alzheimer&apos s Disease Axon Binding Binding Proteins Biochemical Biological Assay Brain Brain Diseases Brain region Calmodulin Characteristics Chemicals Chronic Chronic Disease Coculture Techniques Dendrites Development Diagnosis Diffuse Axonal Injury Disease Electrophysiology (science)Fluorescence Resonance Energy Transfer Glaucoma Health Hippocampus (Brain)Image Inflammation Ion Channel Knockout Mice Light Liquid substance Mechanical Stress Mechanics Mediating Membrane Microtubule-Associated Proteins Microtubules Modeling Multiple Sclerosis Myelin Nerve Degeneration Neurons Output Parkinson Disease Pattern Physiological Process Protein Biochemistry Proteins Ranvier&apos s Nodes Recovery Regulation Research Role Signal Transduction Site Small Interfering RNA Staging Stress Stretching Structure Swelling Synapses Synaptic Transmission Testing Traumatic Brain Injury Varicosity axon injury base disease-causing mutation insight interdisciplinary approach knock-down live cell imaging mild traumatic brain injury mouse model nerve injury neuronal cell body neurotransmission novel patch clamp polarized cell polypeptide presynaptic receptor response tool

项目摘要

PROJECT SUMMARY Little is known about the role of micromechanical stress in regulating neuronal morphological and functional polarity. Diffuse axonal injury caused by mechanical impact displays characteristic axonal varicosities (swelling or beading), which are a prominent feature of traumatic brain injury (TBI). Abundant axonal varicosities are also a key sign for irreversible neurodegeneration in Alzheimer's and Parkinson's diseases, and multiple sclerosis. Under physiological conditions, a lower level of axonal varicosities can be observed in the brain. Although axonal varicosities profoundly affect action potential propagation and synaptic transmission, how they are specifically induced in axons by mechanical stress and regulated in health and disease remains a mystery. Our preliminary studies have led to several novel findings to shed light on this important question. We found that mechanical stress induces varicosity formation in unmyelinated axons, but not in dendrites or myelinated axons of central neurons. This process is unexpectedly rapid and reversible, where a transient receptor potential (TRP) channel acts as the major mechanosensitive (MS) ion channel. We further identified a novel binding protein of this channel, which regulates microtubule (MT) disassembly in response to Ca2+ influx. Moreover, we observed the rapid development of axonal varicosities in the brain of a mouse model of mild TBI. Based on our preliminary results, we propose an original hypothesis that micromechanical stress preferentially induces axonal varicosities in central neurons, and this process is regulated by axonal intrinsic and extrinsic mechanisms. To test this hypothesis, we will use a multidisciplinary approach including novel microbiomechanical assays, protein biochemistry, electrophysiological recording, state-of-the- art imaging, myelin coculture, knockout mice and a mild TBI mouse model. We will determine (Aim 1) whether targeting and activity of MS ion channels regulate polarized mechanosensation in central neurons, (Aim 2) how MT disassembly is induced by intra-axonal Ca2+ increase and in turn leads to varicosity formation, and (Aim 3) whether the pattern of axonal varicosity formation in the mild TBI mouse model is regulated by myelin, the MS channel and its binding protein. This project represents an underexplored research field with many open questions. This research is significant because it will provide novel mechanistic insights into a new form of central neuron polarity, polarized mechanosensation.

项目总结