Although inflammation-induced peripheral sensitization (i.e. increased sensitivity of sensory neurons) can resolve as an injury heals, under pathological conditions this sensitization is maintained and contributes to chronic inflammatory pain. Studies of the cellular mechanisms mediating this maintenance of peripheral sensitization have focused on transcriptional changes that alter protein expression or post-translational modulation of various proteins, especially ion channels. To date, however, these studies have not resulted in new therapeutic approaches for treating chronic inflammatory pain. For this R21 application, we propose a novel mechanism for maintaining sensitization of sensory neurons, i.e. inflammation-induced DNA damage. This damage could result in an alteration in the phenotype of neurons from normal to the sensitized state. Recent studies performed in our laboratory provide support for examining this mechanism, since we have shown that augmenting DNA repair mechanism reverses toxicity in sensory neurons induced by cancer therapies. Furthermore, our preliminary data suggest that inflammation and the inflammatory mediators LPS, MCP-1, and, PGE2, can produce DNA damage in sensory neurons. Thus, we hypothesize that inflammation and inflammatory mediators produce oxidative DNA damage in sensory neurons that contributes to hypersensitivity and that augmenting the base excision repair pathway protects neurons from this damage and thus attenuates the enhanced excitability. To test this hypothesis we propose two specific aims. In studies for the first aim, w will determine whether CFA-induced inflammation or long-term exposure to inflammatory mediators (LPS, MCP-1 or PGE2) in isolated sensory neurons produces reactive oxygen species (ROS) and DNA damage in sensory neurons. We also will determine whether antioxidants or increasing APE1 repair activity (by overexpressing it in sensory neurons) prevents or reverses the DNA damage.
In aim 2, we will determine whether augmenting APE1 activity with overexpression in sensory neurons prevents or reverses peripheral sensitization induced by CFA injection into the rat hindpaw or by long-term exposure to inflammatory mediators (LPS, MCP-1 or PGE2) in isolated sensory neurons. If we demonstrate that DNA repair reverses peripheral sensitization that occurs during inflammation, our findings have important implications for elucidating a novel therapeutic target for treating chronic pain.

Public Health Relevance

The studies outlined in this proposal will examine whether DNA damage in sensory neurons is a novel way in which inflammation or inflammatory mediators will increase the excitability of sensory neurons. We will determine whether increasing DNA repair activity prevents or reverse the long-term increase in activity of sensory neurons that conduct pain signals. If successful, our results could lead to a new target for drug therapy to treat chronic inflammatory pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS091667-01
Application #
8870628
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Oshinsky, Michael L
Project Start
2015-02-01
Project End
2017-01-31
Budget Start
2015-02-01
Budget End
2016-01-31
Support Year
1
Fiscal Year
2015
Total Cost
$234,000
Indirect Cost
$84,000
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Sardar Pasha, Sheik Pran Babu; Sishtla, Kamakshi; Sulaiman, Rania S et al. (2018) Ref-1/APE1 Inhibition with Novel Small Molecules Blocks Ocular Neovascularization. J Pharmacol Exp Ther 367:108-118
Darby, Lisa M; Meng, Hongdi; Fehrenbacher, Jill C (2017) Paclitaxel inhibits the activity and membrane localization of PKC? and PKC?I/II to elicit a decrease in stimulated calcitonin gene-related peptide release from cultured sensory neurons. Mol Cell Neurosci 82:105-117
Shah, Fenil; Logsdon, Derek; Messmann, Richard A et al. (2017) Exploiting the Ref-1-APE1 node in cancer signaling and other diseases: from bench to clinic. NPJ Precis Oncol 1:
Shah, Fenil; Goossens, Emery; Atallah, Nadia M et al. (2017) APE1/Ref-1 knockdown in pancreatic ductal adenocarcinoma - characterizing gene expression changes and identifying novel pathways using single-cell RNA sequencing. Mol Oncol 11:1711-1732
Ding, Jixin; Fishel, Melissa L; Reed, April M et al. (2017) Ref-1/APE1 as a Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia. Mol Cancer Ther 16:1401-1411
Fehrenbacher, Jill C; Guo, Chunlu; Kelley, Mark R et al. (2017) DNA damage mediates changes in neuronal sensitivity induced by the inflammatory mediators, MCP-1 and LPS, and can be reversed by enhancing the DNA repair function of APE1. Neuroscience 366:23-35
Kelley, Mark R; Wikel, James H; Guo, Chunlu et al. (2016) Identification and Characterization of New Chemical Entities Targeting Apurinic/Apyrimidinic Endonuclease 1 for the Prevention of Chemotherapy-Induced Peripheral Neuropathy. J Pharmacol Exp Ther 359:300-309
Logsdon, Derek P; Grimard, Michelle; Luo, Meihua et al. (2016) Regulation of HIF1? under Hypoxia by APE1/Ref-1 Impacts CA9 Expression: Dual Targeting in Patient-Derived 3D Pancreatic Cancer Models. Mol Cancer Ther 15:2722-2732
Georgiadis, Millie M; Chen, Qiujia; Meng, Jingwei et al. (2016) Small molecule activation of apurinic/apyrimidinic endonuclease 1 reduces DNA damage induced by cisplatin in cultured sensory neurons. DNA Repair (Amst) 41:32-41