The role of ENF loss, TLR4 and spinal plasticity in paclitaxel CIPN

 描述(申请人提供)：周围神经病是每一种主要一线化疗药物用于治疗所有最常见类型癌症的主要剂量限制因素，因此每年影响数十万患者。神经病会导致如此痛苦，以至于许多患者将放弃潜在的根治疗法，直接影响他们的生存。化疗所致的周围神经病变(CIPN)难以治疗，通常持续存在于癌症幸存者中，限制了患者的生活质量、康复和恢复生产力。该项目持续的长期目标是确定CIPN的机制，并确定缓解或预防CIPN的潜在治疗干预措施。这个项目的主要假设是化疗药物激活了DRG神经元亚群上的Toll样受体4(TLR4)，从而1)触发了DRG神经元细胞信号的改变，并由启动和维持CIPN的免疫细胞渗透到DRG；2)推动远端CIPN的丢失 3)引起脊髓神经胶质细胞和神经元的激活，从而导致这些细胞的生理不适应变化，进而导致CIPN症状的发生。这一假设将在接受化疗的人类和动物身上进行测试。具体目标1将确定激活DRG中的天然免疫是否是CIPN的关键启动步骤。具体目标2将确定在化疗期间，当周围神经支配密度下降到临界点时，是否会在人类中触发CIPN。具体目标3将确定TLR4和损伤相关分子模式(DAMP)蛋白在推动脊髓背角的不适应性可塑性中的作用，从而导致CIPN。总而言之，该项目将确定化疗引起的周围神经病变的机制，确定患者的危险因素和潜在的新的近期保护和治疗候选方案。因此，该项目将影响数以千计的癌症患者的生活质量、生存和恢复生产力。

 DESCRIPTION (provided by applicant): Peripheral neuropathy is the principal dose-limiting factor for each of the major frontline chemotherapeutic drugs used against all the most common types of cancer and hence affects hundreds of thousands of patients each year. Neuropathy causes such distress that many patients will drop out of potentially curative therapy, directly impacting their survival. Chemotherapy-induced peripheral neuropathy (CIPN) is refractory to treatment and often persists in cancer survivors limiting quality of life, rehabilitation and the return to productivity. The continuing long-term goal of this project is to determine the mechanisms of CIPN and identify potential therapeutic interventions for its relief or prevention. The main hypothesis in this project is that chemotherapeutics activate toll-like receptor 4 (TLR4) on subsets of DRG neurons that 1) trigger altered cellular signaling in DRG neurons and infiltration of the DRG by immune cells that initiate and sustain CIPN; 2) drive the loss of distal epidermal nerve fibers (ENFs) to a critical point associated with onset of CIPN symptoms; and 3) cause activation of spinal glia and neurons that result in maladaptive changes in the physiology of these cells that further contribute to CIPN symptoms. This hypothesis will be tested in humans and animals that receive chemotherapy treatments. Specific Aim 1 will determine whether activation of innate immunity in the DRG is a key initiating step in CIPN. Specific Aim 2 will determine whether CIPN in humans is triggered when peripheral innervation density decreases to a critical point during chemotherapy. Specific Aim 3 will determine the role of TLR4 and damage associated molecular pattern (DAMP) proteins in driving maladaptive plasticity in the spinal dorsal horn contributing to CIPN. In summary this project will define mechanisms of chemotherapy-induced peripheral neuropathy, identify patient risk factors and potential new near-term protective and treatment candidates. This project will therefore impact on the quality of life, survival and the return to productivity of thousands of cancer patients.