(PQ#9) Promoting Axon Stability to Prevent Therapy-induced Peripheral Neuropathy

项目概要/摘要： 治疗诱导的周围神经病变（TIPN）是一种非常常见的，通常是剂量限制性的副作用， 抗癌治疗临床上，TIPN是一种主要的感觉性周围神经病变，其特征在于 麻木、刺痛，通常还有神经性疼痛。这些症状可以持续数年后停止 因此，TIPN可在治疗期间和治疗后显著降低患者的生活质量。 此外，TIPN的发展通常需要减少药物剂量或转换方案， 因此限制了抗癌治疗的有效性。目前，TIPN尚无有效的治疗方法。 轴突缺失是这种神经病变的标志，这表明机制上不同的化疗药物可能 进入一个共同的轴突退化程序我们已经证明SARM 1的遗传抑制， 这个核心轴突变性程序的中央执行者，阻止了小鼠TIPN的发展 长春新碱诱导的周围神经病变模型。SARM 1通路通过触发神经元凋亡诱导轴突丢失 消耗必需的代谢辅因子NAD。在这里，我们试图阻止TIPN的发展， 抵消这种NAD的损失以维持轴突健康。我们还探索了阻止 激活SARM 1作为阻断TIPN发展的新治疗策略。最后，瞄准 如果操纵SARM 1通路不影响肿瘤，则该通路将是TIPN的有用治疗 生长或化疗功效。我们将使用遗传肿瘤模型来探索这一点。如果成功，这 该项目将确定预防TIPN的新治疗策略。

Project Summary/Abstract: Therapy-induced peripheral neuropathy (TIPN) is a very common and often dose-limiting side effect of anti-cancer therapy. Clinically, TIPN is a predominantly sensory peripheral neuropathy characterized by numbness, tingling, and often, neuropathic pain. These symptoms can persist for years after cessation of treatment, and so TIPN can significantly diminish patient's quality-of-life both during and after treatment. Moreover, the development of TIPN often necessitates reducing drug dosage or switching regimens, and therefore limits the effectiveness of anti-cancer therapy. Currently, there are no effective treatments for TIPN. Axon loss is a hallmark of this neuropathy, suggesting that mechanistically distinct chemotherapeutics may feed into a common axonal degeneration program. We have demonstrated that genetic inhibition of SARM1, the central executioner of this core axonal degeneration program, blocks the development of TIPN in a mouse model of vincristine-induced peripheral neuropathy. The SARM1 pathway induces axon loss by triggering depletion of the essential metabolic co-factor NAD. Here we seek to block the development of TIPN by countering this loss of NAD in order to maintain axonal health. We also explore mechanisms to block the activation of SARM1 as novel therapeutic strategies for blocking the development of TIPN. Finally, targeting the SARM1 pathway will be a useful treatment for TIPN if manipulating this pathway does not affect tumor growth or chemotherapeutic efficacy. We will explore this using genetic tumor models. If successful, this project will identify novel treatment strategies for the prevention of TIPN.