Identification of susceptibility to chemotherapy induced peripheral neuropathy using patient stem cell derived sensory neurons

项目概要/摘要 利用患者干细胞鉴定化疗诱导的周围神经病变的易感性 感觉神经元 化疗所致周围神经病变机制的研究进展 （CIPN）是非常有限的，更重要的是，没有办法确定谁处于危险之中。在这一提议中， 我们将测试CIPN体外模型的实用性，该模型使用从患者源性干细胞产生的人类神经元。 研究CIPN风险的细胞。感觉神经元是CIPN中最常受影响的神经元， 从用化疗紫杉醇治疗的患者产生的iPSC系产生，所述患者用化疗紫杉醇治疗，或 而不是开发CIPN。将测量这些神经元对紫杉醇诱导的神经毒性的易感性， 确定CIPN患者的神经元是否更容易受到化疗神经毒性的影响 与年龄、性别和剂量匹配的对照组相比，没有发生CIPN。的感觉神经元 也将暴露于其他类型的化疗剂，其也引起周围神经病变 尽管有不同的刺激机制，但为了确定感觉神经元对 化学疗法诱导的毒性对于某些种类的药物是通用的或特定的。这些发现可能有助于 在治疗前识别有CIPN风险的患者，并了解导致CIPN的因素。 CIPN易感性。

Project Summary/Abstract Identification of susceptibility to chemotherapy induced peripheral neuropathy using patient stem cell derived sensory neurons Current understanding of the mechanisms responsible for chemotherapy induced peripheral neuropathy (CIPN) is extremely limited and more importantly, there is no way of identifying who is at risk. In this proposal, we will test the utility of an in-vitro model of CIPN using human neurons generated from patient-derived stem cells for the study of CIPN risk. Sensory neurons, the neurons most commonly affected in CIPN, will be generated from iPSC lines generated from patients treated with the chemotherapeutic paclitaxel who did, or did not, develop CIPN. The susceptibility of these neurons to paclitaxel-induced neurotoxicity will be measured to determine whether neurons from individuals with CIPN are more vulnerable to chemotherapeutic neurotoxicity than those from their age, gender and dose matched controls who did not develop CIPN. The sensory neurons will also be exposed to other classes of chemotherapeutic agents, which also cause peripheral neuropathy despite distinct antineoplastic mechanisms, to determine whether sensory neuron susceptibility to chemotherapy-induced toxicity is generic or specific to certain classes of drug. These findings could contribute to identifying patients at risk for CIPN prior to their treatment and understanding the factors which contribute to CIPN susceptibility.