Defining TMEM184b-Controlled Pathways in Nerve Terminal Maintenance and Axon Degeneration

定义神经末梢维护和轴突变性中 TMEM184b 控制的通路

基本信息

批准号：
10421073
负责人：
Martha Ruth Chase Bhattacharya
金额：
$ 35.18万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10421073
关键词：
Address Affect Alzheimer&apos s Disease Amino Acids Amyotrophic Lateral Sclerosis Autophagocytosis Autophagosome Axon Axonal Transport Behavior Behavioral Biochemical Biochemistry Biological Biotinylation Cell Survival Cells Cellular biology Cessation of life Charcot-Marie-Tooth Disease Cyclic AMP Data Defect Diabetes Mellitus Diabetic Neuropathies Disease Drosophila genus Eating Electrophysiology (science)Event G-Protein-Coupled Receptors Genetic Genetic Diseases Genetic Epistasis Goals Impairment Inherited Injury Integral Membrane Protein Knowledge Label Life Link Lysosomes MAP Kinase Gene Maintenance Measurement Mediator of activation protein Metabolic stress Mitogen-Activated Protein Kinases Mitotic Modeling Molecular Molecular Analysis Motor Mus Muscle Mutant Strains Mice Natural regeneration Nerve Nerve Block Nerve Crush Nervous system structure Neuraxis Neurodegenerative Disorders Neurons Optic Nerve Organelles Pain Pathway interactions Peripheral Peripheral Nerves Peripheral Nervous System Pharmaceutical Preparations Phenotype Plant Roots Play Process Proteins Research Role Sensory Signal Pathway Signal Transduction Societies Stress Structure Symptoms Synapses Synaptic Transmission System Tactile Testing Tissues Traumatic injury Wallerian Degeneration Work afferent nerve axonal degeneration base beta-arrestin chemotherapy chemotherapy induced neuropathy fly follow-up functional restoration genetic analysis in vitro Assay injured multicatalytic endopeptidase complex mutant nerve injury nervous system disorder neuromuscular neurotoxicity novel p38 Mitogen Activated Protein Kinase pain behavior preservation prevent protein protein interaction recruit response to injury synaptic function therapy design

项目摘要

The overall objective of our work is to understand how nerve terminals and axons are maintained throughout life and how they respond to injury. In the peripheral nervous system (PNS), long primary motor and sensory axons and their terminals are susceptible to a wide variety of pro-degenerative insults, including metabolic stress during diabetes, neurotoxicities of chemotherapy drugs, traumatic injuries, and genetic disorders including Charcot-Marie-Tooth and Amyotrophic Lateral Sclerosis (ALS). In these disorders, terminals and axons are often the first affected structures, and their degeneration precedes cell body death. By mapping out the cellular, genetic, and biochemical landscape of the early events of nerve terminal and axon degeneration, we might identify ways to delay or prevent this degeneration in neurodegenerative disorders. We are focused on the axonal and synaptic functions of TMEM184b, a newly discovered 7-pass transmembrane protein, in the PNS. Loss of TMEM184b in mice causes progressive dystrophies in both motor and sensory nerve terminals, and also causes sensorimotor deficits. In addition to these nerve terminal phenotypes, reduction of TMEM184b in Drosophila or in mice leads to prolonged axon integrity after injury, suggesting TMEM184b is active in the axon degeneration cascade. Accumulations of autophagosomes and lysosomes, compartments responsible for protein and organelle degradation, are seen in mutant tissues. Based on these data, we hypothesize that TMEM184b regulates a step in autophagy. Because autophagy is known to promote axon degeneration and also alter synapse structure, this hypothesis would explain both the axon and synapse phenotypes of TMEM184b mutant mice. Using both mouse and Drosophila systems, we will test our hypothesis with a combination of molecular and genetic analysis, electrophysiology, cell biology, and behavior. In Aim 1, we will ascertain the root causes of the sensorimotor deficits seen in both flies and mice lacking TMEM184b by investigating neuromuscular synaptic transmission and sensory transduction, molecularly characterizing terminal dystrophies, and evaluating peripheral nerve axon transport. In Aim 2, we will probe the cellular and molecular pathways controlled by TMEM184b in cultured neurons and explanted tissues, with a particular focus on linking TMEM184b biological activity to the control of autophagy. In Aim 3, we will identify how TMEM184b contributes to pro-degenerative pathways in injured nerves using genetic epistasis and biochemistry, and we will ask whether TMEM184b's role in axon degeneration is conserved in the central nervous system. In summary, our research will describe a new mechanism of autophagy control in neurons that may underlie early stages of neurodegenerative diseases. This work will contribute to the discovery of new strategies to block nerve terminal and axon degeneration in neurodegenerative disorders.

我们工作的总体目的是了解如何保持神经终端和轴突在整个过程中如何保持生活以及他们如何应对伤害。在周围神经系统（PNS）中，长主电动机和感觉轴突及其终端容易受到多种促成损伤的影响，包括代谢应力在糖尿病期间，化学疗法药物的神经毒性，创伤性损伤和遗传疾病（包括） charcot-marie-tooth和肌萎缩性侧硬化症（ALS）。在这些疾病中，终端和轴突通常是第一个影响的结构及其变性先于细胞体死亡。通过映射细胞，神经终末和轴突变性的早期事件的遗传和生化景观，我们可能确定延迟或防止神经退行性疾病中这种退化的方法。我们专注于TMEM184B的轴突和突触功能，这是一个新发现的7-Pass 跨膜蛋白，在PNS中。小鼠中TMEM184B的损失会导致两种电动机的进行性营养不良和感觉神经末端，还会导致感觉运动缺陷。除了这些神经终端表型，果蝇或小鼠中TMEM184B的降低会导致受伤后轴突完整性延长，提示TMEM184B在轴突变性级联中活跃。自噬体的积累和在突变组织中可见溶酶体，负责蛋白质和细胞器降解的腔室。基于在这些数据上，我们假设TMEM184B调节自噬的一步。因为已知自噬促进轴突变性并改变突触结构，该假设可以解释轴突和 TMEM184B突变小鼠的突触表型。使用小鼠和果蝇系统，我们将通过分子和遗传分析，电生理学，细胞生物学和行为。在AIM 1中，我们将确定通过研究神经肌肉突触传播和感觉转导，分子表征末端营养不良，并评估周围神经轴突传输。在AIM 2中，我们将探测由细胞和分子途径控制的培养的神经元和外植物组织中的TMEM184B，特别着眼于链接TMEM184B生物学自动噬控制的活动。在AIM 3中，我们将确定TMEM184B如何促进促成使用遗传性遗传和生物化学的神经受伤神经的途径，我们将询问TMEM184B的作用是否在中枢神经系统中，轴突变性是保守的。总而言之，我们的研究将描述神经元中自噬控制的新机制神经退行性疾病的早期阶段。这项工作将有助于发现新策略以阻止神经退行性疾病中的神经末端和轴突变性。