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：
8655461
负责人：
Meifan Chen
金额：
$ 5.33万
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 2015-08-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8655461
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）：由大脑和脊髓组成的成年哺乳动物中枢神经系统中轴突的有限能力，是从脊髓损伤中恢复功能性恢复的主要障碍治疗。了解调节神经元内轴突再生轴突的分子成分将有助于鉴定轴突repai的潜在治疗靶标。亮氨酸拉链激酶LZK/MAP3K13是哺乳动物轴突再生的有吸引力的候选调节剂，因为它是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。提出的项目检验了LZK是哺乳动物轴突再生的神经元内阳性调节剂的假设。在第一个目的中，将使用各种神经元细胞系和原发性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的轴突切开术调节，然后鉴定介导LZK对轴突再生的影响的下游信号效应子。在第三个目标中，将在他莫昔芬诱导和感觉神经元特异性的LZK无效小鼠中检查轴突再生中LZK的需求。 LZK过表达促进轴突再生的能力也将在野生型小鼠中研究。建立LZK作为成年哺乳动物中轴突再生的调节剂，并阐明其信号传导成分将为脊髓损伤的治疗干预措施的潜在发展提供分子基础，并具有涉及轴突损伤的某些神经退行性疾病。