TSC2 AND ERK SIGNALING IN MTOR-DEPENDENT REGENERATION AND NEUROPATHIC PAIN

MTOR 依赖性再生和神经病理性疼痛中的 TSC2 和 ERK 信号传导

• 批准号: 8704123
• 负责人: Valeria Cavalli
• 金额: $ 55.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704123
• 关键词: Acute; Acute Pain; Affect; Afferent Neurons; Axon; Biochemical; Biological Assay; Data; Development; Discrimination; Event; Failure; Genetic; Goals; Growth; Healed; Hypersensitivity; In Vitro; Inflammation; Injury; Knock-out; Lead; Link; MAPK1 gene; MAPK3 gene; Maintenance; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Natural regeneration; Nerve Regeneration; Neurologic; Neurons; Nociception; Nociceptors; Pain; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral nerve injury; Physiological; Population; Presynaptic Terminals; Process; Protein Biosynthesis; Protein Isoforms; Proteins; Recovery; Regulation; Role; Signal Pathway; Signal Transduction; System; Testing; Translations; Tuberous sclerosis protein complex; axon growth; axon regeneration; chronic neuropathic pain; chronic pain; healing; human TSC2 protein; in vivo regeneration; injured; insight; mTOR protein; nerve injury; neurological recovery; neuronal cell body; painful neuropathy; programs; protein expression; regenerative; reinnervation; repaired; research study; response; role model; sensory stimulus

DESCRIPTION (provided by applicant): Acute pain in the wake of peripheral injury is an important, adaptive physiological response. Pain helps to reduce re-injury, thus hastening recovery. Acute pain normally resolves when the injury heals. However, in many cases involving damage to peripheral nerves, acute pain transforms into chronic pain, which persists long after wounds have fully healed, and can be severely debilitating. Injury to peripheral nerves elicits a regenerative response and may also lead to long-term sensitization that contributes to the development of chronic pain. Protein synthesis in sensory neurons is required for both axon regeneration and for the development and maintenance of sensitization and pain following injury. Our goal is to gain new insights into the signaling pathways controlling protein synthesis in response to nerve injury to develop strategies that stimulate neurological recovery without coincidently promoting the development of chronic pain. The evolutionarily conserved mammalian Target Of Rapamycin (mTOR), a master regulator of the protein synthesis machinery, and the extracellular signal-regulated kinase (ERK) pathway are linked to both axon regeneration and to the development of neuropathic pain. Activation of mTOR by conditional deletion of the negative regulator tuberin (TSC2) in sensory neurons is sufficient to sustain regenerative growth, but whether it affects the development of nerve injury-induced pain is not known. ERK1/2 signaling is a major upstream regulator or mTOR activity. Although sensitization and regenerative axon growth are two processes known to require protein synthesis, the role or ERK1/2 signaling in regulating protein synthesis in sensory neurons has not been explored. Furthermore, in the studies performed to date, no discrimination was made regarding which ERK isoform, ERK1 or ERK2, is involved in sensitization and regenerative axon growth. Our preliminary data reveal ERK2 as the critical isoform for nociceptor sensitization and as a negative regulator of axon regeneration. This provocative result challenges the current model of the role of ERK1/2 signaling in axon regeneration. We propose here to identify the overlapping molecular events that regulate axon regeneration and the conversion from acute to chronic pain after nerve injury. Specifically, we will determine if ERK signaling regulates protein synthesis in naive or injured primary sensory neurons. We will determine which ERK isoform affects the regenerative ability of sensory neurons and if this effect is dependent on ERK-mediated regulation of protein synthesis. Finally, we will evaluate the effect of TSC2, ERK1 and ERK2 deletion on the development and maintenance of nerve injury-induced pain. Together, these experiments will test whether TSC2 and ERK signaling converge to mTOR-dependent protein translation to regulate nerve regeneration and the development of injury-induced chronic pain.

描述(申请人提供)：外周损伤后的急性疼痛是一种重要的适应性生理反应。疼痛有助于减少再次受伤，从而加速康复。当伤口愈合时，急性疼痛通常会消失。然而，在许多涉及周围神经损伤的病例中，急性疼痛转变为慢性疼痛，在伤口完全愈合后持续很长时间，可能会严重虚弱。对周围神经的损伤会引起再生反应，也可能导致长期的敏感化，从而导致慢性疼痛的发展。感觉神经元的蛋白质合成是轴突再生所必需的，也是损伤后敏感化和疼痛的发展和维持所必需的。我们的目标是获得对神经损伤反应中控制蛋白质合成的信号通路的新见解，以开发刺激神经恢复而不同时促进慢性疼痛发展的策略。进化上保守的哺乳动物雷帕霉素靶蛋白(MTOR)是蛋白质合成机制的主要调节者，细胞外信号调节激酶(ERK)途径与轴突再生和神经病理性疼痛的发生有关。通过有条件地删除感觉神经元中负调控因子tuberin(TSC2)来激活mTOR足以维持再生生长，但它是否影响神经损伤所致疼痛的发展尚不清楚。ERK1/2信号是一种主要的上游调节因子或mTOR活动。虽然敏化和再生轴突生长是两个已知的需要蛋白质合成的过程，但ERK1/2信号在调节感觉神经元蛋白质合成中的作用尚未被探索。此外，在迄今进行的研究中，没有区分ERK亚型中的哪一个，ERK1或ERK2，参与敏化和再生轴突生长。我们的初步数据显示，ERK2是伤害性感受器敏化的关键亚型，也是轴突再生的负调控因子。这一具有挑衅性的结果对目前ERK1/2信号在轴突再生中的作用模型提出了挑战。我们建议确定重叠的分子事件，调节轴突再生和神经损伤后从急性疼痛到慢性疼痛的转化。具体来说，我们将确定ERK信号是否调节幼稚或受损的初级感觉神经元的蛋白质合成。我们将确定哪个ERK亚型影响感觉神经元的再生能力，以及这种影响是否依赖于ERK介导的蛋白质合成调节。最后，我们将评估TSC2、ERK1和ERK2缺失在神经损伤性疼痛的发生和维持中的作用。总之，这些实验将测试TSC2和ERK信号是否会聚到mTOR依赖的蛋白质翻译，以调控神经再生和损伤诱导的慢性疼痛的发展。