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 患者对于一些患者，这种并发症妨碍了最佳治疗，因此危及了治疗的机会。 治愈，而许多患者发展为永久性的，无法治疗的疼痛和严重的感觉缺陷， 降低癌症患者和幸存者的生活质量。导致轴突退化的机制 CIPN中的感觉症状刚刚开始被定义，目前还不清楚是否 CIPN的基础机制可以从化学疗法的抗肿瘤功效中生物学地解决。 在这种背景下，我们以前在这项赠款下的研究表明， CIPN中轴突Ca+2和Ca+2依赖性钙蛋白酶的激活。基于这些发现，我们将 确定联系在一起的过程1）紫杉醇或其他化疗对 微管，2）激活参与轴突破坏的分子，加上化合物的损失， 促进轴突存活和3）开放位于长轴突内的Ca+2通道。我们的研究利用了 啮齿类动物感觉神经元在隔室培养，免疫功能正常的小鼠与紫杉醇敏感的乳房 癌症，以及从患有严重CIPN或CIPN的患者制备的新的人iPSC衍生的感觉神经元培养物。 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， 治疗CIPN而不损害紫杉醇的抗肿瘤疗效，我们将开发新的 治疗化合物。由于CIPN中轴突变性的过程与疾病中所见相似， 包括遗传性神经病，ALS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先进治疗。

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.