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: 8212064
• 负责人: Mark R. Kelley
• 金额: $ 40.51万
• 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 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212064
• 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，通常称为化学脑和周围神经病。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，包括脱碱基核酸内切酶 1/氧化还原因子（Ape1/Ref-1 或 Ape1），已被证明是化疗和电离辐射引起的氧化和烷化剂损伤的主要 DNA 修复途径。红外）。此外，Ape1 与许多转录因子相互作用，特别是 NF:B、AP1 和 p53，通过氧化还原信号传导调节它们的功能。在神经元中，这些转录因子介导许多与神经元存活有关的蛋白质的表达，并改变对损伤和炎症的反应的兴奋性。因此，Ape1 可以通过其 DNA 修复和/或其氧化还原功能在维持神经组织稳态中发挥关键作用。这项工作的总体假设是，Ape1 可以增强化疗或 IR 损伤后神经元的存活和功能，并通过最大限度地减少 DNA 的烷基化和氧化损伤以及调节 AP1、NFkB 和第 53 页。我们将使用原代大鼠中枢神经系统（海马）和感觉神经元细胞（背根神经节或 DRG）确定 Ape1 是否参与与化疗和 IR 相关的神经毒性和神经元功能。我们将在正常情况下以及添加癌症化疗药物和 IR 后减少或增强这些神经元中的 Ape1 表达，并确定对神经元功能和存活的各个方面的影响。我们还将使用仅具有氧化还原或修复功能的 Ape1 突变蛋白或仅抑制修复或氧化还原活性的药物来确定 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 的氧化还原活性是否会改变化疗和 IR 后神经元培养物中下游应激反应因子（例如 AP1、NFkB 和 p53）的活性。本应用中的实验将为神经认知（“化疗脑”）机制研究奠定基础。 ”）以及化疗和 IR 后患者经历的周围神经病变。了解癌症治疗期间的神经保护机制对于为患者提供有助于减轻这些严重副作用的神经保护至关重要。

项目成果

Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy.

DNA 碱基切除修复蛋白 APE1 在顺铂、奥沙利铂或卡铂诱导的感觉神经病中的作用。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Kelley, Mark R;Jiang, Yanlin;Guo, Chunlu;Reed, April;Meng, Hongdi;Vasko, Michael R
• 通讯作者: Vasko, Michael R

APE1, the DNA base excision repair protein, regulates the removal of platinum adducts in sensory neuronal cultures by NER.

APE1 是 DNA 碱基切除修复蛋白，通过 NER 调节感觉神经元培养物中铂加合物的去除。

• 发表时间: 2015-09
• 作者: Kim HS;Guo C;Thompson EL;Jiang Y;Kelley MR;Vasko MR;Lee SH
• 通讯作者: Lee SH

Suppression of choroidal neovascularization through inhibition of APE1/Ref-1 redox activity.

通过抑制 APE1/Ref-1 氧化还原活性来抑制脉络膜新生血管形成。

• DOI: 10.1167/iovs.14-14451
• 发表时间: 2014-06-26
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Yue Li;Xiuli Liu;T. Zhou;M. Kelley;P. Edwards;Hua Gao;X. Qiao
• 通讯作者: X. Qiao

Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization.

抑制 APE1/Ref-1 氧化还原活性可挽救人视网膜色素上皮细胞免受氧化应激并减少脉络膜新生血管形成。

• 发表时间: 2014
• 影响因子: 11.4
• 作者: Li, Y;Liu, X;Zhou, T;Kelley, M R;Edwards, P;Gao, H;Qiao, X
• 通讯作者: Qiao, X

Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture.

紫杉醇改变培养物中大鼠感觉神经元的降钙素基因相关肽的诱发释放。

• 发表时间: 2014-03
• 影响因子: 5.3
• 作者: Pittman, Sherry K;Gracias, Neilia G;Vasko, Michael R;Fehrenbacher, Jill C
• 通讯作者: Fehrenbacher, Jill C