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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121168-05
Application #
8212064
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
2008-04-01
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$405,107
Indirect Cost
$134,825
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Kelley, Mark R; Logsdon, Derek; Fishel, Melissa L (2014) Targeting DNA repair pathways for cancer treatment: what's new? Future Oncol 10:1215-37
Kelley, Mark R; Jiang, Yanlin; Guo, Chunlu et al. (2014) Role of the DNA base excision repair protein, APE1 in cisplatin, oxaliplatin, or carboplatin induced sensory neuropathy. PLoS One 9:e106485
Domenis, Rossana; Bergamin, Natascha; Gianfranceschi, Giuseppe et al. (2014) The redox function of APE1 is involved in the differentiation process of stem cells toward a neuronal cell fate. PLoS One 9:e89232
Li, Yue; Liu, Xiuli; Zhou, Tongrong et al. (2014) Suppression of choroidal neovascularization through inhibition of APE1/Ref-1 redox activity. Invest Ophthalmol Vis Sci 55:4461-9
Li, Y; Liu, X; Zhou, T et al. (2014) Inhibition of APE1/Ref-1 redox activity rescues human retinal pigment epithelial cells from oxidative stress and reduces choroidal neovascularization. Redox Biol 2:485-94
Pittman, Sherry K; Gracias, Neilia G; Vasko, Michael R et al. (2014) Paclitaxel alters the evoked release of calcitonin gene-related peptide from rat sensory neurons in culture. Exp Neurol 253:146-53
Zhang, Jun; Luo, Meihua; Marasco, Daniela et al. (2013) Inhibition of apurinic/apyrimidinic endonuclease I's redox activity revisited. Biochemistry 52:2955-66
Kelley, Mark R; Georgiadis, Millie M; Fishel, Melissa L (2012) APE1/Ref-1 role in redox signaling: translational applications of targeting the redox function of the DNA repair/redox protein APE1/Ref-1. Curr Mol Pharmacol 5:36-53
Luo, Meihua; Zhang, Jun; He, Hongzhen et al. (2012) Characterization of the redox activity and disulfide bond formation in apurinic/apyrimidinic endonuclease. Biochemistry 51:695-705
Gracias, N G; Cummins, T R; Kelley, M R et al. (2011) Vasodilatation in the rat dorsal hindpaw induced by activation of sensory neurons is reduced by paclitaxel. Neurotoxicology 32:140-9

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