Role of Stress Granule Protein Aggregation in Axon Regeneration

应激颗粒蛋白聚集在轴突再生中的作用

• 批准号: 10406395
• 负责人: JEFFERY L TWISS
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406395
• 关键词: Acute; Affective; Aftercare; Attenuated; Axon; Binding; Case Study; Development; G3BP1 gene; Health; In Vitro; Individual; Measures; Mentors; Messenger RNA; Modeling; Neurons; Nociception; Nociceptors; Pain; Patients; Peripheral nerve injury; Phosphorylation; Process; Protein Biosynthesis; Proteins; Quality of life; RNA; RNA, Messenger, Stored; Research; Research Personnel; Rodent; Role; Schools; Signal Transduction; Translational Regulation; Translational Research; Translations; United States; axon growth; axon regeneration; design; disability; experience; functional outcomes; in vivo; injured; nerve injury; nerve supply; painful neuropathy; peripheral nerve regeneration; protein aggregation; response to injury; stress granule

Peripheral nerve injuries are common with more than 200,000 new cases reported each year in the United States alone. Only about 10% of these individuals regain much function. Nerve injury significantly impacts long-term quality of life, and most injured individuals seek continued treatments for associated disabilities and pain. The most common explanation for poor functional outcomes is the slow and inefficient process of axon regeneration. Proteins synthesized locally in axons contribute to peripheral nerve regeneration by providing retrograde signals for injury responses and supporting axon regrowth locally. We have shown that mRNAs are stored in PNS axons in RNA-protein aggregates that contain the stress granule protein G3BP1. G3BP1 protein can drive stress granule aggregation, and G3BP1 phosphorylation blocks stress granule assembly. G3BP1 binds to mRNAs in axons and attenuates their translation. We have discovered exogenous agents and endogenous signals that trigger disassembly of axonal G3BP1 aggregates. The exogenous agents specifically increase axonal protein synthesis and accelerate axon growth rates in vitro and in vivo. However, translational regulation of axonal mRNAs has been demonstrated in models of neuropathic pain, and nerve injury patients frequently seek additional treatment after peripheral nerve injury for the development of neuropathic pain. Whether acute disassembly of G3BP1 RNAs within nociceptive neurons will lead to or exacerbate neuropathic pain is unknown and is a key step toward translatability of this type of therapy. This ‘Research Supplement to Promote Diversity in Health-Related Research’ is designed to bring translational research experience to a post- baccalaureate fellow with mentoring from a team of one junior and two senior investigators. This will prepare the fellow for graduate school and strengthen her applications.

周围神经损伤很常见，每年报告的新病例超过20万例。 仅美国一国。这些人中只有10%左右恢复了大部分功能。神经损伤 显著影响长期生活质量，大多数受伤的人寻求继续 相关残疾和疼痛的治疗。对贫穷最常见的解释是 功能结果是轴突再生缓慢而低效的过程。蛋白质 轴突局部合成通过提供逆行作用促进周围神经再生 损伤反应和局部支持轴突再生的信号。我们已经证明了mRNAs 储存在三叉神经节轴突中的包含应激颗粒蛋白的RNA-蛋白质聚合体中 G3BP1。G3BP1蛋白可促进应激颗粒聚集和G3BP1磷酸化 块体应力颗粒组装。G3BP1与轴突中的mRNAs结合并减弱其 翻译。我们已经发现外源因子和内源信号会触发 轴突G3BP1集合体的解体。外源性药物特别增加轴突 在体外和体内，蛋白质合成和加快轴突生长速度。但是，翻译 轴突mrna的调节已在神经病理性疼痛和神经病变模型中得到证实。 损伤患者在周围神经损伤后经常寻求额外的治疗 神经病理性疼痛的发展。G3BP1 RNA的急性分解是否存在于 伤害性神经元会导致或加剧神经病理性疼痛是未知的，也是关键的一步 这种疗法的可译性。这本《促进多样性的研究副刊》 与健康相关的研究旨在将翻译研究体验带到后- 学士学位研究员，由一名初级调查人员和两名高级调查人员组成的团队提供指导。 这将为这位研究员进入研究生院做准备，并加强她的申请。