Neurotrophin regulation of mRNA localization and translation in axons.

神经营养素对轴突中 mRNA 定位和翻译的调节。

• 批准号: 8391341
• 负责人: Sara J. Fenstermacher
• 金额: $ 2.95万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391341
• 关键词: 3' Untranslated Regions; Afferent Neurons; Apoptotic; Axon; Characteristics; Data; Dendrites; Detection; Development; Disease; Elements; Environment; Family member; Genes; Genetic Transcription; Growth Factor; Health; Imagery; In Vitro; Individual; Knowledge; Life; Maintenance; Mediating; Messenger RNA; Methods; Mitochondria; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Peripheral; Peripheral Nerves; Play; Process; Proteins; Regulation; Reporter; Research; Research Proposals; Role; Spinal Ganglia; Structure; Techniques; Testing; Therapeutic; Translating; Translations; Work; axonal degeneration; base; in vivo; insight; neuron loss; neuronal cell body; neuronal survival; neurotrophic factor; novel; prevent; research study; therapeutic target

DESCRIPTION (provided by applicant): Neurotrophins play a critical role in supporting neuronal viability throughout life. This role requires that neurotrophins promote the health of cel bodies and also the health of extensive dendrites and axons characteristic of mature neurons. Recent studies have demonstrated that the mechanisms which promote axonal viability only partially overlap with those that regulate cell body survival. The proposed work focuses on neurotrophin regulation of axonal viability, and the role of the specialized Bcl2 family member Bcl-w in this process. Work from the sponsor's lab has demonstrated that Bcl-w mRNA and protein are expressed at high levels in axons of dorsal root ganglia (DRG) sensory neurons, and that loss of Bcl-w results in selective degeneration of axons in vivo. Furthermore, Bcl-w expression is regulated by neurotrophin stimulation, and in particular, by neurotrophin stimulation of the axons. Together, these data suggest that Bcl-w is a specialized axonal survival factor that mediates the effects of neurotrophins on axonal viability. The two aims presented in this research proposal build on previous studies from the sponsor, and will directly test how neurotrophins regulate Bcl-w mRNA and protein in axons, in order to understand mechanisms for maintaining axonal health. Aim1: To test the hypothesis that the 3'UTR is critical for targeting bcl-w mRNA to axons. To do this, the bcl-w 3'UTR will be tested for its abilty to localize a reporter sequence to axons. Aim 2: To test the hypothesis that neurotrophins regulate local translation of bcl-w in axons. To do so, a novel method which provides several advantages over current techniques of studying translation in axons will be used. In preliminary studies I have demonstrated effective use of this method in DRG neurons and compartmented cultures. Local synthesis of Bcl-w in axons may provide a mechanism for mediating the sustained effect of neurotrophins on axonal viability and maintenance. This work will develop our understanding of how neurotrophins promote survival and health of distinct cellular compartments and the mechanisms by which axons are maintained throughout life. Understanding the mechanisms by which neurotrophins regulate axonal viability are essential to understanding mechanisms of axonal degeneration and finding therapeutic targets for disorders of neurodegeneration. PUBLIC HEALTH RELEVANCE: Growth factors, called neurotrophins, are required for the survival and maintenance of neurons throughout an individual's lifetime. The proposed research will develop our understanding for the specific mechanisms by which neurotrophins support health of neurons with long axons, such as peripheral sensory neurons, which carry vital information about the environment. This work will be critical for understanding mechanisms of axonal degeneration and for developing therapeutic treatments for neurodevelopmental and neurodegenerative disorders.

描述（由申请人提供）：神经营养蛋白在支持一生的神经元生存力中起着至关重要的作用。该作用要求神经营养蛋白促进CEL身体的健康以及成熟神经元的广泛树突和轴突的健康。最近的研究表明，促进轴突生存能力的机制仅部分与调节细胞存活的机制重叠。拟议的工作着重于轴突生存力的神经营养蛋白调节，以及专门的BCL2家族成员Bcl-W在此过程中的作用。赞助商实验室的工作表明，Bcl-W mRNA和蛋白质在背根神经节（DRG）感觉神经元中以高水平表达，而Bcl-W的损失会导致体内轴突的选择性变性。此外，Bcl-W表达受神经营养蛋白刺激，尤其是轴突的神经营养蛋白刺激来调节。总之，这些数据表明Bcl-W是一种专门的轴突存活因子，可介导神经营养蛋白对轴突生存能力的影响。这项研究建议中提出的两个目标是基于赞助商的先前研究，并将直接测试神经营养蛋白如何调节轴突中的Bcl-W mRNA和蛋白质，以了解维持轴突健康的机制。 AIM1：测试3'UTR对于将Bcl-W mRNA靶向轴突至关重要的假设。为此，将对Bcl-W 3'UTR进行测试，以使其将报道序列定位到轴突。目的2：测试神经营养蛋白调节轴突中Bcl-W局部翻译的假设。为此，将使用一种与当前在轴突中研究翻译技术相比的新方法。在初步研究中，我证明了在DRG神经元和隔室培养物中有效使用了这种方法。轴突中BCl-W的局部合成可能提供了一种介导神经营养蛋白对轴突生存能力和维持的持续作用的机制。这项工作将发展我们对神经营养蛋白如何促进不同细胞室的生存和健康以及轴突在整个生命中保持的机制的理解。了解神经营养蛋白调节轴突生存力的机制对于理解轴突变性的机制和寻找神经变性疾病的治疗靶点至关重要。 公共卫生相关性：在一个人的一生中生存和维持神经元所必需的生长因素，称为神经营养蛋白。拟议的研究将对神经营养蛋白支持长轴突的神经元（例如外周感觉神经元）的健康的特定机制发展我们的理解，这些神经元具有有关环境的重要信息。这项工作对于理解轴突变性的机制以及开发神经发育和神经退行性疾病的治疗方法至关重要。