Regenerative and Degenerative Responses to Axonal Injury

对轴突损伤的再生和退行性反应

• 批准号: 8039157
• 负责人: CATHERINE A COLLINS
• 金额: $ 32.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039157
• 关键词: Address; Animal Model; Autophagocytosis; Axon; Axonal Transport; Biological Assay; Cell Nucleus; Data; Defect; Distal; Drosophila genus; Event; Gene Expression; Genetic; Goals; Health; Image; Importins; Injury; JNK-activating protein kinase; Life; MAPK8 gene; Measures; Mediating; Methods; Microtubules; Modeling; Molecular; Motor; Motor Neurons; Mutation; N-terminal; Names; Nerve Crush; Neurodegenerative Disorders; Neurons; Nuclear; Pathway interactions; Phosphotransferases; Play; Process; Proteins; Regenerative Medicine; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Spinal cord injury; Structure; System; Testing; Ubiquitin; Vertebrates; Work; axon growth; axonal degeneration; base; in vivo; injured; insight; interest; multicatalytic endopeptidase complex; neuronal cell body; public health relevance; regenerative; research study; response; response to injury; retrograde transport; scaffold; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): An important goal for regenerative medicine is to understand how neurons sense and respond to axonal damage. Due to the highly polarized structure of axons, axonal transport machinery, which delivers cellular cargo from one part of the axon to the other, plays important roles in the cellular responses to injury. One major response is the induction of new axonal growth. This regenerative response requires the retrograde transport of signaling molecules from the injury site to the nucleus. Another major response is degeneration of the severed distal 'stump'. This may also rely on axonal transport machinery, since defects in the process of axonal transport usually accompany (and often proceed) axonal degeneration in neurodegenerative disorders. To study mechanisms of injury signaling, degeneration, and axonal transport, we take advantage of the powerful genetics of Drosophila as a model organism, in which we have developed a new injury paradigm that allows mechanistic characterization of injury response pathways in vivo. Our assays include nuclear reporters, which measure changes in gene expression in injured neurons, and live imaging assays that measure axonal transport of specific cargo in axons. The focus of this study is the role and mechanism of a conserved axonal kinase, named Wallenda (Wnd) in Drosophila, DLK in vertebrates. Recent studies indicate that this kinase regulates both regenerative and degenerative responses to axonal injury. Our recent observations suggest that Wnd may function by regulating the transport of specific cargo in axons. The goals of this study are to identify the Wnd-regulated cargo, and determine the role(s) of this cargo in both retrograde signaling and degeneration. PUBLIC HEALTH RELEVANCE: Axonal damage triggers both regenerative and degenerative responses in neurons. We are studying a molecular pathway, which has recently been discovered to function in both the regrowth of axons after injury and also in degeneration of the part of the axon that has been severed from the cell body. The findings from this work will be important both for treatment of spinal cord injuries and also for understanding mechanisms of neurodegenerative disorders.

描述（由申请人提供）：再生医学的一个重要目标是了解神经元如何感知和响应轴突损伤。由于轴突的高度极化结构，轴突运输机制将细胞货物从轴突的一部分运送到另一部分，在细胞对损伤的反应中起重要作用。一个主要的反应是诱导新的轴突生长。这种再生反应需要信号分子从损伤部位逆行转运到细胞核。另一个主要的反应是远端断端的退化。这也可能依赖于轴突运输机制，因为轴突运输过程中的缺陷通常伴随（并且经常进行）神经退行性疾病中的轴突变性。为了研究损伤信号传导、变性和轴突运输的机制，我们利用果蝇作为模式生物的强大遗传学，在该模式生物中，我们开发了一种新的损伤范例，该范例允许对体内损伤反应途径进行机械表征。我们的分析包括核报告，测量损伤神经元中基因表达的变化，以及测量轴突中特定货物的轴突运输的活体成像分析。本研究的重点是一种保守的轴突激酶的作用和机制，在果蝇中称为Wallenda（Wnd），在脊椎动物中称为DLK。最近的研究表明，这种激酶调节轴突损伤的再生和退行性反应。我们最近的观察表明，Wnd可能通过调节轴突中特定货物的运输来发挥作用。本研究的目的是鉴定Wnd调节的货物，并确定这种货物在逆行信号传导和变性中的作用。 公共卫生相关性：轴突损伤触发神经元的再生和退行性反应。我们正在研究一种分子途径，最近发现它在损伤后轴突的再生和从细胞体切断的轴突部分的退化中起作用。这项工作的发现对于脊髓损伤的治疗和理解神经退行性疾病的机制都很重要。