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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：
9919006
负责人：
Martha Ruth Chase Bhattacharya
金额：
$ 37.65万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9919006
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.

我们工作的总体目标是了解神经末梢和轴突是如何在整个过程中维持的