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

(PQ9)APE1和BER在化疗引起的周围神经病变中的机制作用

• 批准号: 9901467
• 负责人: JILL C FEHRENBACHER
• 金额: $ 53.76万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901467
• 关键词: Acute; Address; Afferent Neurons; American Society of Clinical Oncology; Anatomy; Animal Model; Antineoplastic Agents; Attenuated; Base Excision Repairs; Behavior; Behavioral; Biological Markers; Cells; Chemicals; Chemotherapy-induced peripheral neuropathy; Cisplatin; Clinical; DNA Damage; DNA Repair; DNA glycosylase; Data; Development; Disease; Dose-Limiting; Electrophysiology (science); Etiology; Exposure to; FDA approved; Genetic Transcription; Genome; Incidence; Knowledge; Lesion; Measures; Mediating; Mitotic; Molecular; Neurons; Neuropathy; Neurotoxins; Oxidation-Reduction; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Prevention; Process; Production; Proteins; Quality of life; Repair Complex; Reporting; Research; Role; Secondary to; Sensory; Severities; Stimulus; Survivors; Symptoms; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Treatment Efficacy; Withdrawal; Work; acute symptom; anticancer treatment; base; cancer therapy; chemotherapy; clinically significant; design; drug mechanism; effective therapy; endonuclease; in vivo; neurochemistry; neuroprotection; neurotoxic; neurotoxicity; new therapeutic target; novel; novel therapeutics; prevent; repair enzyme; repaired; side effect; tool; transcriptome

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.

项目概要/摘要 随着癌症治疗不断变得更加有效，患者生存率不断提高，我们正在认识到 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 具有重要临床意义的是化疗引起的周围神经病变（CIPN），它可以 严重到需要减少或停止治疗，从而影响治疗。 此外，CIPN 可以在治疗停止后持续很长时间，并且在许多情况下是不可逆转的。 缺乏有效的治疗方法来预防或逆转 CIPN，使这一问题变得更加复杂。 对 CIPN 缺乏有效的预防或治疗是不了解 CIPN 的直接后果 因此，我们要研究“什么是神经毒性”这一具有争议性的问题。 癌症治疗引起的严重疾病发展的分子和/或细胞机制 不良后遗症？”将在我们的研究中使用动物模型和一系列测量终点来解决 感觉神经元功能的变化与 CIPN 的临床症状相似，大多数 CIPN 会随着时间的推移而发生。 初始治疗后几乎没有急性症状，但随着继续治疗，严重程度会增加。 神经病发作表明药物随着时间的推移会产生累积效应，从而导致长期的 神经功能的改变，重要的是检查累积的机制。 此前，我们已经证明，减少化疗药物可能会导致神经毒性。 通过减少脱嘌呤/脱嘧啶的表达来增强 DNA 碱基切除修复 (BER) 途径的活性 核酸内切酶/氧化还原因子（APE1/Ref-1或APE1）加剧抗癌治疗产生的神经毒性， 而增强 APE1 的修复活性则减弱了神经毒性。这些数据支持这样的观点： DNA 损伤是化疗药物影响感觉神经元功能的关键机制。 事实上，在有丝分裂后细胞（例如神经元）中，DNA 损伤可能会导致蛋白质产生异常 除非 DNA 损伤得到修复，从而逆转 DNA 的异常转录效应，否则这种情况将持续存在。 因此，我们发现 APE1 是保护神经元免受癌症侵害的关键蛋白质。 疗法，增强 APE1 DNA 修复活性将预防和逆转化疗引起的 此外，充分了解 DNA 损伤和感觉神经元功能的改变。 BER 途径逆转这种损害的机制将导致新的识别 CIPN 预防或治疗的目标 为了解决这些假设，我们提出了三个目标。 确定增强 APE1 体内修复活性是否可以预防或逆转感觉中的 DNA 损伤 神经元以及抗癌药物引起的感觉神经元功能的后续变化 以及确定介导 APE1 诱导的孤立感觉神经元神经保护的机制。