Role of leucine zipper bearing kinase LZK in mammalian axon regeneration

亮氨酸拉链激酶 LZK 在哺乳动物轴突再生中的作用

基本信息

批准号：
8525672
负责人：
Meifan Chen
金额：
$ 5.1万
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：
2013
资助国家：
美国
起止时间：
2013-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8525672
关键词：
Adult Afferent Neurons Axon Axotomy Biochemical Brain Caenorhabditis elegans Calcium Cell Line Development Drosophila melanogaster Environment Event Genetic Homologous Gene Human Impairment In Vitro Individual Injury Invertebrates Knockout Mice Leucine Zippers MAP Kinase Gene Mammals Mediating Microtubules Molecular Mus Natural regeneration Neuraxis Neurites Neurodegenerative Disorders Neurons Output Paralysed Pathway interactions Phosphotransferases Recovery Recovery of Function Regulation Reporter Role Signal Pathway Signal Transduction Spinal Cord Spinal cord injury Tamoxifen Testing Therapeutic Intervention Ursidae Family Weather axon growth axon regeneration base effective therapy in vivo inhibitor/antagonist injured insight nervous system disorder novel overexpression programs public health relevance regenerative response response to injury therapeutic target therapy development

项目摘要

DESCRIPTION (provided by applicant): The limited ability of axons in the adult mammalian central nervous system, consisting of the brain and spinal cord, to regenerate is a major obstacle to functional recovery from spinal cord injuries for which there is currently no effective treatment. Understanding the molecular components regulating neuron-intrinsic capacity to regenerate axons will facilitate the identification of potential therapeutic targets for axon repai. Leucine zipper-bearing kinase LZK/MAP3K13 is an appealing candidate regulator of mammalian axon regeneration because it is one of two mammalian homologues of the invertebrate dual leucine zipper-bearing kinase DLK-1/Wallenda required for the regenerative response in Caenorhabditis elegans and Drosophila melanogaster. The proposed project tests the hypothesis that LZK is a neuron- intrinsic positive regulator of mammalian axon regeneration. In the first aim, the effect of overexpressing or depleting LZK on neurite extension and regeneration will be established in vitro using various neuronal cell lines and primary neurons. In the second aim, axotomy- dependent regulation of LZK will be examined in vitro and in vivo by biochemical and immunohistochemical approaches, followed by identification of the downstream signaling effectors mediating the effect of LZK on axon regeneration. In the third aim, the requirement for LZK in axon regeneration will be examined in tamoxifen-inducible and sensory neuron-specific LZK null mice. The ability of LZK overexpression to promote axon regeneration will also be investigated in wildtype mice. Establishment of LZK as a regulator of axon regeneration in adult mammals and elucidation of its signaling components will provide the molecular basis for potential development of therapeutic interventions for spinal cord injuries and certain neurodegenerative diseases involving axonal damage.

描述（由申请人提供）：成年哺乳动物中枢神经系统（由大脑和脊髓组成）中轴突的再生能力有限，是脊髓损伤后功能恢复的主要障碍，目前尚无有效的治疗方法治疗。了解调节神经元再生轴突的内在能力的分子成分将有助于识别轴突修复的潜在治疗靶点。亮氨酸拉链激酶 LZK/MAP3K13 是哺乳动物轴突再生的一个有吸引力的候选调节因子，因为它是线虫和果蝇再生反应所需的无脊椎动物双亮氨酸拉链激酶 DLK-1/Wallenda 的两个哺乳动物同源物之一。拟议的项目测试了 LZK 是哺乳动物轴突再生的神经元内在正调节因子的假设。第一个目标是使用各种神经元细胞系和原代神经元在体外建立过表达或耗尽 LZK 对神经突延伸和再生的影响。在第二个目标中，将通过生化和免疫组织化学方法在体外和体内检查 LZK 的轴切依赖性调节，然后鉴定介导 LZK 对轴突再生的影响的下游信号传导效应器。第三个目标是在他莫昔芬诱导型和感觉神经元特异性 LZK 缺失小鼠中检查轴突再生中 LZK 的需求。还将在野生型小鼠中研究 LZK 过度表达促进轴突再生的能力。 LZK 作为成年哺乳动物轴突再生调节剂的建立及其信号成分的阐明将为脊髓损伤和某些涉及轴突损伤的神经退行性疾病的治疗干预措施的潜在开发提供分子基础。