TIMP-1 as a Modulator of Inflammatory Pain

The prevalence and financial impact of chronic pain is substantial, and the presence of unresolved inflammation predicts its development. However, the mechanisms underlying unresolved inflammation are not well understood. Therefore, investigation of pathways involved in resolution of inflammatory pain could identify novel therapeutic targets. Our lab has previously identified tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) as an inhibitor of inflammatory hypersensitivity. In this work, we explore the mechanisms through which TIMP-1 achieves this. In our first set of experiments, we sought to identify targets downstream of TIMP-1 that were also involved in inflammation. We performed whole transcriptome RNA sequencing found that transcriptomic alterations in the dorsal root ganglion (DRG) due to inflammation and deletion of TIMP-1 converge prominently on dysregulation of ion channel expression. This suggests that TIMP-1 regulates inflammatory pain by attenuating inflammation-induced upregulation of ion channel expression in nociceptors. To confirm this connection, in our next set of experiments, we found that exogenous application of TIMP-1 attenuates the presence of spontaneous inflammatory pain and downregulates expression of the ion channel, Nav1.7 in the DRG. In our last set of experiments, we sought to further define this connection and asked whether TIMP -1 could regulate pain and ion channel expression through its known interactome. We found that peripheral knockdown of CD63, a receptor for TIMP-1, was sufficient to promote spontaneous inflammatory pain and increase expression of Nav1.7 mRNA in the DRG. These findings define a mechanism of TIMP-1-mediated attenuation of inflammatory hypersensitivity and suggest that further work exploring the effects of TIMP-1-related pathways could provide insight into the resolution of inflammatory pain.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2024

Author dc:creator

• McDonald, Rena

Advisor dc:contributor.advisor

• Baumbauer, Kyle

• Neurosciences
• Inflammation
• Ion channel
• Nav1.7
• Pain
• Scn9a
• TIMP-1

Language dc:language.iso

en

Dc Identifier Other

http://dissertations.umi.com/ku:19742

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/38380