The Role of Ape1 in Neurotoxicity of Cancer Treatments

Ape1 在癌症治疗神经毒性中的作用

• 批准号: 8021035
• 负责人: Mark R. Kelley
• 金额: $ 40.35万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8021035
• 关键词: Accounting; Adverse effects; Afferent Neurons; Alkylating Agents; Alkylation; Antineoplastic Agents; Base Excision Repairs; Cells; Clinical; DNA; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; Data; Etiology; Exposure to; Genetic Transcription; Genome; Hippocampus (Brain); Homeostasis; Impaired cognition; Inflammation; Injury; Ionizing radiation; Maintenance; Malignant Neoplasms; Measures; Mediating; Methods; Mitochondria; Mutation; Neuraxis; Neurocognitive; Neurons; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Play; Preparation; Production; Proteins; Rattus; Reactive Oxygen Species; Role; Secondary to; Sensory; Signal Transduction; Site; Slice; Small Interfering RNA; Spinal Cord; Spinal Ganglia; Study Section; Therapeutic Effect; Tissues; Transcription Factor AP-1; Treatment Protocols; Virus Diseases; Work; base; biological adaptation to stress; cancer therapy; chemobrain; chemotherapeutic agent; chemotherapy; crosslink; endonuclease; experience; inhibitor/antagonist; mitochondrial genome; mutant; neuronal survival; neuroprotection; neurotoxic; neurotoxicity; neurotransmitter release; overexpression; oxidative damage; prevent; repaired; research study; response; response to injury; small molecule; transcription factor

DESCRIPTION (provided by applicant): Numerous neurotoxic side effects of cancer treatments include cognitive dysfunction, commonly called chemobrain and peripheral neuropathy. The mechanisms for these side-effects and ways to protect neurons remain to be elucidated. The DNA base excision repair (BER) pathway including the abasic- endonuclease1/redox factor (Ape1/Ref-1 or Ape1) has been shown to be the major DNA repair pathway for oxidative and alkylating agent damage that occurs with chemotherapy and ionizing radiation (IR). Additionally, Ape1 interacts with a number of transcription factors, especially NF:B, AP1 and p53 to regulate their function through redox signaling. In neurons, these transcription factors mediate the expression of a number of proteins involved in neuronal survival and altered excitability in response to injury and inflammation. Thus, Ape1 could play a critical role in maintaining homeostasis in neuronal tissue through its DNA repair and/or its redox function. The overall hypothesis of the proposed work is that Ape1 acts to enhance neuronal survival and function after injury by chemotherapy or IR and helps to maintain normal neuronal function by minimizing alkylation and oxidative damage to DNA as well as by regulating the activity of AP1, NFkB and p53. We will determine if Ape1 is involved in the neurotoxicity and neuronal function associated with chemotherapy and IR using primary rat central nervous system (hippocampal) and sensory neuronal cells (dorsal root ganglia or DRG). We will reduce or augment Ape1 expression in these neurons under normal and following the addition of cancer chemotherapeutic agents and IR and ascertain the effects on various aspects of neuronal function and survival. We also will use Ape1 mutant proteins that only have either the redox or repair functions or drugs that inhibit only the repair or redox activity to ascertain which functions of Ape1 are critical for neuroprotection/function. Finally, we will determine whether the redox activity of Ape1 alters the activity of downstream stress response factors such as AP1, NFkB and p53 in neuronal cultures following chemotherapy and IR.Experiments in this application will form the basis for mechanistic studies into neurocognitive ("chemobrain") and peripheral neuropathy experienced by patients following chemotherapy and IR. Understanding the mechanism for neuroprotection during cancer therapy will be critical in providing patients with neuroprotection that can help alleviate these serious side effects.

描述（由申请人提供）：癌症治疗的许多神经毒性副作用包括认知功能障碍，通常称为Chemobrain和外周神经病。这些副作用的机制和保护神经元的方法仍有待阐明。 DNA碱基切除修复（BER）途径（包括abasic-核酸内核酸酶1/氧化还原因子（APE1/REF-1或APE1））已证明是用于化学疗法和电离辐射（IR）发生的氧化和烷基化剂损伤的主要DNA修复途径。此外，APE1与许多转录因子，尤其是NF：B，AP1和P53相互作用，以通过氧化还原信号传导调节其功能。在神经元中，这些转录因子介导了许多参与神经元存活的蛋白质的表达，并响应损伤和炎症而改变了兴奋性。因此，APE1可以通过其DNA修复和/或其氧化还原功能来维持神经元组织中的稳态中发挥关键作用。拟议工作的总体假设是，APE1通过化学疗法或IR损伤后提高神经元存活和功能，并通过最大程度地减少对DNA的烷基化和氧化损害以及调节AP1，NFKB和p53的活性来帮助维持正常的神经元功能。我们将使用原发性大鼠中枢神经系统（海马）和感觉神经元细胞（背根神经节或DRG）确定APE1是否参与与化学疗法和IR相关的神经毒性和神经元功能。我们将在正常情况下降低或增强这些神经元中的APE1表达，并在添加癌症化学治疗剂并确定对神经元功能和生存的各个方面的影响。我们还将使用仅具有仅抑制修复或氧化还原活性的氧化还原或修复功能或药物的APE1突变蛋白来确定APE1的哪些功能对于神经保护/功能至关重要。最后，我们将确定APE1的氧化还原活性会改变化学疗法和IR的神经元培养物中下游应力反应因素（例如AP1，NFKB和P53）的活性是否会构成对神经认知（Chemobrain”（“ Chemobrain”）和外周神经性神经疗法的机械性研究的基础。了解癌症治疗期间神经保护的机制对于为患者提供有助于减轻这些严重副作用的患者至关重要。