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Roles of a novel MAPKKK in axonal responses to injury in the mammalian CNS

新型 MAPKKK 在哺乳动物中枢神经系统损伤轴突反应中的作用

基本信息

批准号：
8946155
负责人：
Binhai Zheng
金额：
$ 33.91万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8946155
关键词：
Address Alleles Animal Model Axon Axotomy Biochemical Caenorhabditis elegans Calcium Cessation of life Data Development Distal Drosophila genus Event Gene Deletion Genetic Growth Inhibitors Homologous Gene Human In Vitro Injury Invertebrates Knowledge Leucine Zippers Link MAP Kinase Kinase Kinase Mammals Mediating Modeling Molecular Mus Natural regeneration Nematoda Nerve Regeneration Nervous system structure Neuraxis Neurites Neurologic Neurons PTEN gene Patients Peripheral Peripheral Nervous System Phase Phosphotransferases Play Population Quality of life Reagent Recovery of Function Regulation Research Role Sensory Signal Pathway Signal Transduction Spinal Spinal Cord Spinal cord injury Stroke System Testing Therapeutic Wallerian Degeneration axon growth axon regeneration axonal degeneration central nervous system injury dorsal column fly gain of function genetic manipulation improved in vivo in vivo imaging injured insight loss of function mutant novel overexpression peripheral nerve regeneration public health relevance regenerative repaired response response to injury therapeutic development therapeutic target two-photon

项目摘要

DESCRIPTION (provided by applicant): The limited axonal growth after central nervous system (CNS) injury is the principal cause of no or limited functional recovery after spinal cord injury in humans. While earlier studies emphasized the importance of neuron-extrinsic mechanisms, recent development in the field highlighted the central role of neuron-intrinsic control of axon growth and regeneration after CNS injury. Among neuron-intrinsic regulators, there are factors that sense and mediate the injury signals to elicit diverse responses in differen neuronal populations. Recent discoveries in model organisms such as the nematode and the fruit fly indicate a critical role for a MAP kinase kinase kinase (MAPKKK, or MAP3K), DLK, in axon degeneration and regeneration. There are two sequence homologues in mammals: DLK (also known as MAP3K12) and LZK (also known as MAP3K13). Several studies indicate that mammalian DLK/MAP3K12 is important in axonal responses to injury. Little is known about the other homologue LZK/MAP3K13. Our preliminary studies strongly indicate that LZK regulates axon growth. Here we test the hypothesis that LZK is an important regulator of axonal responses to injury in the mammalian nervous system. We will test the effect of loss of function and gain of function genetic manipulations of LZK in different injury models. In this context, we will also examine any functional redundancy or synergy between DLK and LZK by combined genetic manipulations. To this end, we have generated both loss and gain of function alleles for DLK and LZK in mice. We will examine injury-induced axon degeneration, regeneration (axonal growth from injured neurons) and sprouting (axonal growth from uninjured neurons) with a number of injury models in the CNS, supplemented by injury models in the PNS (peripheral nervous system). Finally, we will examine potential interaction between the LZK and DLK signaling pathways with other neuron- intrinsic (e.g. PTEN) regulators of axon growth. Together, these studies will reveal the endogenous role of the LZK and DLK signaling, and assess the therapeutic potential of activating LZK and DLK signaling in promoting axonal repair after CNS injury.