The Role of Protease-Activated Receptors (PARs) in Spinal Cord Injury and Repair
As cell surface receptors, protease-activated receptors (PARs) endow cells with the ability to respond, or to over-respond, to the rapidly changing proteolytic microenvironment that occurs at sites of central nervous system (CNS) trauma, inflammation and blood-brain barrier breakdown. Protease-activated receptors are seven transmembrane-spanning cell-surface receptors that are activated by enzyme cleavage in their extracellular domain leading to activation of heterotrimeric G proteins (GPCRs) and regulation of cell-signaling cascades that direct cell behavior.
The central hypothesis being studied in Dr. Scarisbrick's Neuroregeneration and Neurorehabilitation Laboratory states, protease-activated receptors in the CNS regulate critical cellular responses after injury and can be targeted therapeutically to prevent secondary injury and to promote an environment favorable to repair, regeneration and rehabilitation. In addition, our new data suggest that PARs regulate the generation of stem cells in the adult CNS and therefore can directly impact the regenerative capacity of the brain and spinal cord. The lab is using genetic and pharmacological loss and gain of function approaches to define the actions of PAR1 and PAR2 in mediating injury and repair responses across neurons, astrocytes and myelinating oligodendroglia, including dissection of the signaling mechanisms involved.
The long-term goal is to identify PARs as targets for pharmacotherapy to improve regeneration and functional outcomes after CNS injury.
This research is funded by the National Institutes of Health (NIH): NIH, National Institute of Neurological Disorders and Stroke (NINDS), 5R01NS052741-08 "Role of Protease Activated Receptors in Spinal Cord Injury and Repair."