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

• 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
• 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

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（由脑和脊髓组成）中轴突再生能力有限，是脊髓损伤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内在能力的分子组分将有助于确定轴突修复的潜在治疗靶点。亮氨酸拉链激酶LZK/MAP 3 K13是哺乳动物轴突再生的一个有吸引力的候选调节因子，因为它是秀丽隐杆线虫和黑腹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。该项目旨在验证LZK是哺乳动物轴突再生的神经元内源性正调节因子的假设。在第一个目标中，将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，将通过生物化学和免疫组织化学方法在体外和体内检查LZK的轴突切断依赖性调节，随后鉴定介导LZK对轴突再生的作用的下游信号传导效应物。在第三个目标中，将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对LZK的需求。还将在野生型小鼠中研究LZK过表达促进轴突再生的能力。建立LZK作为成年哺乳动物轴突再生的调节剂，并阐明其信号传导组分，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的潜在发展提供分子基础。