The Role of Tissue Plasminogen Activator in a Mouse Spinal Cord Injury Model

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DESCRIPTION (provided by applicant): TBI is a significant public health concern. It represents one of the leading causes of chronic disability and lost productivity in individuals under the age of 45 in industrialized countries. TBI often leads to decades of cognitive, behavioral, emotional, and physical dysfunction. Yet treatment options for TBI remain limited and current therapies and Pharmaceuticals provide little benefit. Part of the reason for the lack of efficacy in TBI treatments is the gap in understanding that remains in the study of TBI. Identifying the underlying causes of chronic disability in TBI represents the first step in identifying potential therapeutic targets to treat patients with this disabling disease. Doing so would relieve both individual suffering and the healthcare costs associated with decades of disability. One potential mechanism that leads to persistant dysfunction is alterations in neurotransmitters, receptors, and cellular signaling proteins. Our research focuses on one such potential cellular protein, dopamine and cAMP regulated phosphoprotein 32 (DARPP-32). DARPP-32 plays an extremely important role by integrating signaling from dopamine and glutamate, among other neuretransmitter systems, and indirectly altering many important cellular events including ERK and CREB signaling, NMDA receptors, and the Na/K ATPase. DARPP-32 alters phosphorylation of ERK, CREB, NMDA receptors, and the Na/K ATPase indirectly by affecting the activity of protein kinase a (PKA) and protein phosphatase 1 (PP1). Inhibition of PKA or PP1 is dependent upon the phosphorylation state of DARPP-32 at Thr34 and Thr75 DARPP-32. We hypothesize that TBI causes a decrease in DARPP-32 phosphorylation at Thr34. We hypothesize that this TBI induced decrease in phosphorylation at DARPP-32/Thr34 will remove its inhibition upon PP1 and increase its inhibition of PKA. The increase in PP1 activity will cause decreased phosphorylation of ERK and CREB thereby reducing their activity. A reduction in ERK and CREB activity is associated with reduced transcription of important neurotrophic factors. The decrease in PKA activity will reduce its phosphorylation activity with subsequent decreases in Na/K ATPase phosphorylation and NMDA receptor phosphorylation. PUBLIC HEALTH RELEVANCE:V Alterations in the phosphorylation state of Na/K ATPase and NMDA receptors have important implications for cell membrane and osmotic homeostasis and cellular glutamate responses. We hypothesize that these events are dependent upon DARPP-32 expression.