(PQ9)Mechanistic Role of APE1 and BER in chemotherapy-induced peripheral neuropathy

项目总结/摘要 随着癌症治疗随着患者生存率的提高而变得越来越有效，我们认识到， 对治疗过程和患者生活质量产生负面影响的治疗临床后果 和幸存者具有主要临床意义的是化疗引起的周围神经病变（CIPN）， 严重到必须减少或停止治疗，因此可能危及治疗。 此外，CIPN可以在治疗停止后持续很长时间，并且在相当数量的患者中是不可逆的。 患者使这个问题更加复杂的是缺乏有效的治疗方法来预防或逆转CIPN。的 缺乏对CIPN的有效预防或治疗是不了解CIPN的直接后果。 导致神经毒性的机制。因此，研究“什么是 分子和/或细胞机制的发展，癌症治疗诱导的严重 不良后遗症？”将在我们的研究中使用动物模型和一系列终点测量 感觉神经元功能的变化与CIPN的临床症状平行。大多数CIPN随着时间的推移而发展 在初始治疗后几乎没有任何急性症状，但随着持续治疗严重程度增加。延迟 在神经病发作中的作用表明，随着时间的推移，药物会产生累积效应， 神经元功能的改变。因此，重要的是要检查累积的机制， 暴露于化疗药物可能导致神经毒性。之前，我们证明了减少 DNA碱基切除修复（BER）途径的活性，通过减少脱嘌呤/脱嘧啶 核酸内切酶/氧化还原因子（APE 1/Ref-1或APE 1）加剧了抗癌治疗产生的神经毒性， 而增强APE 1的修复活性可减轻神经毒性。这些数据支持这样一种观点， DNA损伤是化疗药物改变感觉神经元功能的关键机制。 事实上，在有丝分裂后的细胞（例如神经元）中，DNA损伤可能导致异常的蛋白质产生 除非DNA损伤被修复，否则这种蛋白质会被维持，从而逆转DNA损伤的异常转录效应。 神经毒素因此，我们假设APE 1是保护神经元免受癌症侵害的关键蛋白质 增强APE 1 DNA修复活性将预防和逆转化疗诱导的 感觉神经元功能的改变。此外，充分了解DNA损伤和 BER途径逆转这种损伤的机制将导致识别新的 CIPN预防或治疗的靶点。为了解决这些假设，我们提出了三个目标， 确定增强体内APE 1修复活性是否能预防或逆转感觉神经细胞中的DNA损伤。 神经元和随后由抗癌药物给药引起的感觉神经元功能的改变 以及确定介导APE 1诱导的离体感觉神经元的神经保护的机制。

PROJECT SUMMARY / ABSTRACT As cancer treatments continue to become more effective with increases in patient survival, we are recognizing clinical consequences of therapy that negatively impact the course of therapy and the quality of life of patients and survivors. Of major clinical significance is chemotherapy-induced peripheral neuropathy (CIPN), which can be severe enough to necessitate reducing or stopping treatment and thus can compromise therapy. Furthermore, CIPN can continue long after therapy is stopped and is irreversible in a significant number of patients. Compounding this problem is a lack of effective treatments available to prevent or reverse CIPN. The lack of effective prevention or treatment for CIPN is a direct consequence of not understanding the mechanisms that cause the neurotoxicity. As such, examining the provocative question of “What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae?” will be addressed in our studies using animal models and an array of endpoints measuring changes in sensory neuronal function which parallel clinical symptoms of CIPN. Most CIPN develops over time with few if any acute symptoms after initial therapy, but increases in severity with continued therapy. The delay in onset of neuropathy suggests that there is an aggregate effect of drugs over time that results in a long-term alteration in neuronal function. Consequently, it is important to examine the mechanisms by which cumulative exposure to chemotherapeutics might result in neurotoxicity. Previously, we demonstrated that reducing the activity of the DNA base excision repair (BER) pathway by reducing expression of the apurinic/apyrimidinic endonuclease/redox factor (APE1/Ref-1 or APE1) exacerbated neurotoxicity produced by anticancer treatment, whereas augmenting the repair activity of APE1 attenuated the neurotoxicity. These data support the notion that DNA damage is a critical mechanism by which the function of sensory neurons is altered by chemotherapeutics. Indeed, it is likely that in post-mitotic cells (e.g. neurons) DNA damage could result in abnormal protein production that is maintained unless the DNA damage is repaired, reversing the aberrant transcriptional effects of the neurotoxins. Therefore, we hypothesize that APE1 is a critical protein for protecting neurons from cancer therapies and that augmenting APE1 DNA repair activity will prevent and reverse chemotherapy-induced alterations in sensory neuronal function. Furthermore, fully understanding the DNA damage and the mechanisms by which the BER pathway reverses this damage will lead to the identification of novel targets for CIPN prevention or therapy. To address these hypotheses, we propose three aims which will determine whether augmenting APE1 repair activity in vivo prevents or reverses DNA damage in sensory neurons and the subsequent alterations in sensory neuronal function caused by anticancer drug administration as well as determining the mechanisms mediating APE1-induced neuroprotection of isolated sensory neurons.