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

基本信息

批准号：
8514568
负责人：
Valeria Cavalli
金额：
$ 53.47万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/8514568
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

项目摘要

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（由申请人提供）：周围损伤后的急性疼痛是一种重要的自适应生理反应。疼痛有助于减少受伤，从而加剧康复。急性疼痛通常会在损伤愈合时解决。然而，在许多情况下，涉及对周围神经损害的损害，急性疼痛转化为慢性疼痛，在伤口完全愈合后很长一段时间，可能会严重使人衰弱。外周神经的损伤引起了再生反应，也可能导致长期敏感性，这有助于慢性疼痛的发展。轴突再生以及损伤后的敏化和疼痛的发展和维持需要感觉神经元中的蛋白质合成。我们的目标是获得有关控制蛋白质合成的信号通路的新见解，以响应神经损伤，以制定刺激神经系统恢复的策略，而不必巧合地促进慢性疼痛的发展。蛋白质合成机制的主要调节剂和细胞外信号调节激酶（ERK）途径的进化保守的乳腺霉素（MTOR）的哺乳动物靶标与轴突再生和神经性疼痛的发育有关。通过有条件地缺失在感觉神经元中负调节蛋白（TSC2）的MTOR激活足以维持再生生长，但是它是否影响神经损伤引起的疼痛的发展。 ERK1/2信号传导是主要的上游调节器或MTOR活性。尽管敏化和再生轴突生长是已知需要蛋白质合成的两个过程，但尚未探索在调节感觉神经元中蛋白质合成中的作用或ERK1/2信号传导。此外，在迄今为止所进行的研究中，关于ERK同工型，ERK1或ERK2的研究尚无歧视，参与敏化和再生轴突生长。我们的初步数据揭示了ERK2是伤害感受器敏化的关键同工型，并且是轴突再生的负调节剂。这种挑衅性的结果挑战了ERK1/2信号在轴突再生中作用的当前模型。我们在这里提议确定调节轴突再生的重叠分子事件以及神经损伤后急性疼痛的转化。具体而言，我们将确定ERK信号传导是否调节幼稚或受伤的原发性神经元中的蛋白质合成。我们将确定哪种ERK同工型会影响感觉神经元的再生能力，以及该作用是否取决于ERK介导的蛋白质合成调节。最后，我们将评估TSC2，ERK1和ERK2缺失对神经损伤引起的疼痛的发展和维持的影响。总之，这些实验将测试TSC2和ERK信号传导是否会收敛于MTOR依赖性蛋白质翻译，以调节神经再生和损伤引起的慢性疼痛的发展。