The goal of our proposed Small Project is to develop a long-term in vivo imaging methodology to assess the contribution of PAK1 signaling to dendritic spine dysgenesis in neuropathic pain after SCI. Long-term in vivo assessment of spinal cord neurons with multiphoton microscopy will powerfully advance the West Haven VA RR&D Center?s capabilities toward translational studies in chronic pain and related neurological diseases. We will carry out two objectives to address the goal of this Project. In Objective 1, we will establish a live imaging model that will expand our ability to investigate dynamic changes in dendritic spine plasticity associated with neuropathic pain following SCI. Live imaging of spinal cord tissue in animal models of other neurological diseases is an established procedure that we will adapt for use in an SCI-pain model. Extending the capabilities of this imaging system, we will acquire the hardware necessary to establish a long- term in vivo imaging solution in our Center and perform experiments to validate the use of this methodology in a study of dendritic spine plasticity in the superficial dorsal horn associated with pain after SCI. In Objective 2, we will perform a study using the FDA approved Pak1-inhibitor, romidepsin to determine whether targeting Pak1 relieves neuropathic pain after SCI. Our previous work has demonstrated that disruption of Rac1-activity reduces dendritic spine abnormalities and neuropathic pain. However, the clinical utility of Rac1 as a therapeutic target is limited and has been largely disregarded as a candidate molecule in clinical trials. Emerging evidence from clinical and preclinical studies demonstrate that Pak1, a downstream effector of Rac1, contributes to chronic pain. Interestingly, Pak1 has also been implicated in dendritic spine dysgenesis in a spectrum of neuropsychiatric diseases. To determine whether targeting Pak1 relieves neuropathic pain after SCI, we will perform a functional study using romidepsin. To assess romidepsin drug-response on dendritic spine profiles, we will employ the long-term in vivo imaging approach developed in Objective 1. In summary, this project will firmly establish a whole-animal in vivo imaging system in our Center, which will position us strongly to launch translational studies in chronic neurological disease and injury (Objective 1). It will also provide a proof-of-principle for translational studies that target PAK1 in SCI-induced neuropathic pain, using the FDA approved compound, romidepsin (Objective 2).
Of the >250,000 Americans with SCI, about 42,000 are U.S. Veterans who are eligible for medical care and other benefits from the Department of Veterans Affairs. 50-80% of individuals with SCI experience clinically significant pain. In this project, we will develop a long-term in vivo imaging methodology to assess the contribution of PAK1 signaling to dendritic spine dysgenesis and neuropathic pain after SCI. Results from this study will firmly establish a whole-animal in vivo imaging system at the West Haven VA RR&D VA Center, which will position us strongly to launch translational studies in chronic neurological disease and injury. Moreover, because an overall goal of our work is to translate our findings to the clinic as rapidly as possible, this project will also provide a proof-of-principle for translational studies that target Pak1 in SCI- induced neuropathic pain, using the FDA approved compound, romidepsin.
