ABSTRACT
Pain is the primary reason why people seek medical care, with an estimated 116 million Americans suffering
from chronic and poorly treated pain. Opioids and other drugs targeting the neuronal pathways of pain remain
the gold standards today. However, it is now clear that neurons are not the only players that drive the
establishment and maintenance of pain, and glial cells surrounding neurons are emerging as promising targets
for the treatment of chronic pain. There is increasing evidence that satellite glial cells (SGCs) surrounding
neurons in sensory ganglia modulate sensory processing and are particularly important for chronic pain. Our
long-term goal is to have a better understanding SGCs, and leverage this knowledge to target specific glial
signaling as a mean to identify new therapeutic strategies and reduce the use of opioids for the treatment of
clinical pain. The objective of this application is to study and validate the tissue inhibitor of metalloproteinase 3
(TIMP3) signaling in SGCs as a novel therapeutic target for acute and chronic pain. TIMP3 has unique plethoric
functions in inhibiting matrix metalloproteinases, the tumor necrosis factor-a-converting enzyme, and the
vascular endothelial growth factor receptor 2. Because these enzymes and receptor have all been implicated in
some extend in inflammation and pain, we hypothesize that the expression of the tissue inhibitor of
metalloproteinase 3 (TIMP3) in SGCs is critical for the neuroimmune homeostasis in sensory ganglia, as well as
for the development of pain. We propose to use multiple gain- and loss-of-function approaches in combination
with a battery of behavioral, electrophysiological, and biochemical analyses to validate TIMP3 signaling for the
treatment of acute and chronic pain. Specifically, we will test our hypothesis by the following specific aims: Aim
1 will establish the roles of TIMP3 signaling in pain and peripheral neuroimmune responses. Aim 2 will investigate
and validate TIMP3 signaling in various animal models of acute and chronic pain. Aim 3 will investigate and test
various drugs targeting TIMP3 signaling in human SGC cultures. Given the expression of TIMP3 in human SGCs
and the strong validation of multiple small-molecules targeting TIMP3 signaling, including FDA-approved drugs,
in various animal models of pain and in cultured human SGCs, we are confident that the successful completion
of our research will have a rapid and positive impact on the millions of patients suffering of pain and at risk of
opioid abuse.
