Poorly managed pain creates an enormous burden on our healthcare system and produces tremendous human suffering. Following an injury, pain is caused by the production of inflammatory cytokines that induce changes in the excitability of nociceptor neurons. A better understanding of molecular mechanisms that facilitate nociceptor plasticity is vital for improved pain treatment. Post-transcriptional gene control has emerged as a dominant theme in pain induced plasticity. We focus on Poly(A) binding proteins (PABPs), a conserved family of 3? end associated factors that regulate translation initiation and play prominent roles in development and memory. We will determine binding specificities for PABPs present in dorsal root ganglion (DRG) neurons using an unbiased next- generation sequencing approach. This information will be used to generate a novel class of chemically stabilized RNAs called specificity-derived competitive inhibitor oligonucleotides (SPOT-ONs). Unlike genome editing or RNA interference, SPOT-ONs are well tolerated and bypass the need for host-factors as they function as ?decoys?. A major advantage of pharmacological inhibition as opposed to targeted gene disruption is the ability to simultaneously impair multiple homologues in a larger gene family. Our preliminary findings indicate that a bi- specific PABP SPOT-ON provides robust anti-hyperalgesic effects in vivo. Based on this finding, we hypothesize that PABPs are crucial mediators of plasticity in nociceptors. We describe preliminary development of SPOT- ONs which reduce protein synthesis in nociceptors and act specifically on poly(A)-mediated mRNA translation (Aim 1). We probe PABP mechanism of action through examination of localized translation and global identification of targets in nociceptors (Aim 2). Finally, we determine how PABP inhibition impacts nociceptor excitability and behavioral responses to injury (Aim 3).

Public Health Relevance

Poorly managed pain creates an enormous burden on our healthcare system and produces tremendous human suffering. Limited treatment strategies have resulted in an opioid epidemic. This research investigates molecular and behavioral impacts of targeted inhibition of a conserved family of translation factors as potential targets for pain treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS100788-01
Application #
9282915
Study Section
Special Emphasis Panel (ZRG1-IFCN-B (03))
Program Officer
Oshinsky, Michael L
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
1
Fiscal Year
2017
Total Cost
$399,428
Indirect Cost
$138,364
Name
University of Texas-Dallas
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
800188161
City
Richardson
State
TX
Country
United States
Zip Code
75080