The Role of Ape1 in Neurotoxicity of Cancer Treatments

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，通常称为化疗和周围神经病变。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（Ape 1/Ref-1或Ape 1），已被证明是化疗和电离辐射（IR）引起的氧化和烷化剂损伤的主要DNA修复途径。此外，Ape 1与许多转录因子，特别是NF：B、AP 1和p53相互作用，通过氧化还原信号调节它们的功能。在神经元中，这些转录因子介导参与神经元存活的许多蛋白质的表达以及响应于损伤和炎症而改变的兴奋性。因此，Ape 1可以通过其DNA修复和/或其氧化还原功能在维持神经元组织的稳态中发挥关键作用。所提出的工作的总体假设是，Ape 1在化疗或IR损伤后起增强神经元存活和功能的作用，并通过最小化对DNA的烷基化和氧化损伤以及通过调节AP 1、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Ape 1是否参与与化疗和IR相关的神经毒性和神经元功能。我们将减少或增加Ape 1在这些神经元中的表达，在正常和加入癌症化疗药物和IR后，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Ape 1突变蛋白或仅抑制修复或氧化还原活性的药物，以确定Ape 1的哪些功能对神经保护/功能至关重要。最后，我们将确定Ape 1的氧化还原活性是否会改变下游应激反应因子（如AP 1）的活性，NFkB和p53在神经元培养化疗和IR后。（“chemobrain”）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将是至关重要的，为患者提供神经保护，可以帮助减轻这些严重的副作用。

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.