Axonal transport and chemotherapy induced peripheral neuropathy

摘要 化疗引起的周围神经病变(CIPN)是许多癌症的痛苦和衰弱的后遗症 病人。对于一些患者来说，这种并发症阻碍了最佳治疗，因此危及 治愈，而许多患者出现永久性的、无法治疗的疼痛和严重的感觉障碍， 危及癌症患者和幸存者的生活质量。导致轴突变性的机制 CIPN的感官症状才刚刚开始定义，目前还不清楚 CIPN的机制可以通过化疗的抗肿瘤效应在生物学上得到解决。 在这种背景下，我们以前在这笔赠款下进行的研究表明，增加 CIPN中轴突钙离子与钙依赖的钙蛋白酶的激活在这些发现的基础上，我们将 确定联系在一起的过程1)紫杉醇或其他化疗药物对 微管，2)与轴突破坏有关的分子的激活，加上 促进轴突存活和3)开放位于长轴突内的钙通道。我们的研究利用了 紫杉醇敏感乳房免疫活性小鼠隔室培养的啮齿动物感觉神经元 癌症和从严重CIPN或患者制备的新的人类IPSC来源的感觉神经元培养 来自对CIPN耐药的患者。使用这些创新的方法，我们将确定治疗目标 在不影响紫杉醇抗肿瘤疗效的情况下治疗CIPN，我们将开发新的 治疗性化合物。由于CIPN的轴突变性过程与疾病相似 包括遗传性神经病、肌萎缩侧索硬化症和阿尔茨海默病，我们的见解和治疗方法将 许多其他使人衰弱的疾病的高级治疗。

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating sequela for many cancer patients. For some patients this complication prevents optimal therapy and so jeopardizes the chance for a cure, while many patients develop permanent, untreatable pain and severe sensory deficits that seriously compromise quality of life for cancer patients and survivors. The mechanisms that cause axon degeneration and sensory symptoms in CIPN are just beginning to be defined, and it is not yet clear whether the mechanisms that underlie CIPN can be biologically resolved from anti-neoplastic efficacy of chemotherapy. Against this backdrop, our previous studies under this grant have demonstrated a central role for increased axonal Ca+2 and activation of Ca+2-dependent calpain proteases in CIPN. Building on these findings we will identify the processes linking together 1) the direct effects of paclitaxel or other chemotherapies on microtubules, 2) activation of molecules implicated in axon destruction, plus the loss of compounds that promote axon survival and 3) opening of Ca+2 channels located within the long axons. Our studies make use of rodent sensory neurons in compartmented cultures, immunocompetent mice with paclitaxel-sensitive breast cancer, and new human iPSC-derived sensory neuron cultures prepared from patients with severe CIPN or from patients resistant to CIPN. Using these innovative approaches we will identify therapeutic targets for treating CIPN without compromising the anti-neoplastic efficacy of paclitaxel and we will develop novel therapeutic compounds. Since the process of axon degeneration in CIPN is similar to that seen in diseases including hereditary neuropathy, ALS, and Alzheimer’s disease, our insights and therapeutic approaches will advance treatment for many additional debilitating diseases.