Subcellular and molecular machinery underlying de novo protein synthesis in regenerating axons

再生轴突中蛋白质从头合成的亚细胞和分子机制

• 批准号: 355356-2008
• 负责人: VanMinnen, Jan
• 金额: $ 2.91万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2008
• 资助国家: 加拿大
• 起止时间: 2008-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=402492
• 关键词: Subcellular; molecular; machinery; underlying; de

Peripheral nerve injury (trauma, neuropathic disorders) in humans is common and often debilitating. While peripheral nerves do regenerate better than that of central nervous system, recovery is often incomplete, misdirected or associated with incapacitating neuropathic pain. Despite extensive efforts aimed at defining the nature of an injury response, the precise cellular and molecular mechanisms remain however, poorly defined. Thus, one of the main objectives of this proposal is to define the cellular and molecular mechanisms underlying an injury response, and those that promote nerve regeneration in a rodent model of nerve injury. Central to all regenerative responses is the protein synthetic machinery, which is required not only to inform the nucleus that an injury has occurred but also to synthesize proteins that are essential for new growth and regeneration - a number of which are synthesized locally in the axonal compartment. Based on our preliminary results (where we showed that a bona vide rough endoplasmic reticulum and Golgi apparatus are absent in axons), we hypothesize that axons synthesize proteins through a mechanism that is distinct from that of somal protein synthesis. We seek to determine whether all translational components needed for co-translational targeting of proteins into the ER are indeed: a) present in axons, b) how they are organized at the subcellular level, and c) how they direct local protein synthesis. Secondly, we will determine whether these elements of the proteins synthetic machinery increase in injured and regenerating axons and then determine their cellular origin. In view of our recent data, in which we demonstrated that glia cells can "export" polyribosomes to injured axons, we anticipate an unexpected new role for glia cells in directing protein synthesis in axons. Taken together, these results will shed new light on fundamental mechanisms by which axons respond to injury signals, and in the future may pave the way for novel treatment strategies to promote nerve repair after trauma.

周围神经损伤（创伤、神经性疾病）在人类中是常见的并且常常使人衰弱。虽然周围神经确实比中枢神经系统更好地再生，但恢复通常是不完全的，错误的或与失能性神经性疼痛相关。尽管广泛的努力旨在定义损伤反应的性质，但精确的细胞和分子机制仍然定义不清。因此，本提案的主要目标之一是定义损伤反应的细胞和分子机制，以及在啮齿动物神经损伤模型中促进神经再生的机制。所有再生反应的核心是蛋白质合成机制，它不仅需要通知细胞核已经发生损伤，而且还需要合成新生长和再生所必需的蛋白质-其中一些是在轴突隔室中局部合成的。基于我们的初步结果（我们发现，一个良好的粗面内质网和高尔基体是在轴突缺席），我们假设，轴突合成蛋白质的机制是不同的，从体蛋白质合成。 我们试图确定是否所有翻译所需的蛋白质共翻译靶向到ER的组件确实是：a）存在于轴突，B）它们是如何组织在亚细胞水平，和c）它们如何指导局部蛋白质合成。其次，我们将确定这些蛋白质合成机制的元素是否在受损和再生轴突中增加，然后确定它们的细胞起源。鉴于我们最近的数据，其中我们证明，神经胶质细胞可以“出口”多核糖体受伤的轴突，我们预计一个意想不到的新的作用，神经胶质细胞在指导蛋白质合成的轴突。总之，这些结果将为轴突对损伤信号做出反应的基本机制提供新的线索，并且在未来可能为促进创伤后神经修复的新治疗策略铺平道路。