It is increasingly evident that serine proteases such as plasmin and tissue plasminogen activator (tPA) as well as protease activated receptors (PARs) have a role in the central nervous system (CNS). Recent findings suggest a role for serine proteases and their receptors in normal brain function as well as a potential role in pathological situations such as stroke or head trauma in which the blood brain barrier is compromised. In addition, the brain expresses several unique serine proteases, but their physiological role and substrates in the CNS are unknown. The overall goalof the experiments outlined in this proposal is to expand our understanding of serine protease signaling cascades inthe CNS, and to explore the mechanism by which the blood serine protease, plasmin, may influenceneurodegenerabon when the blood brain barrier is compromised. To accomplish this, three separate lines ofinvestigabon will be initiated. First, immunocytochemistry will be performed in rat brain bssue to determine theprotease activated receptor 1 (PAR1) protein distribution as well as subcellular localization. Second, heterologousexpression systems as well as mouse brain tissue from wild type and PAR1-/- mice will be employed to determine ifthe CNS produces endogenous actvators/inactivators of PAR1. The third goal is to determine the mechanism ofplasmin-mediated potentiation of NMDA receptor responses using electrophysiological and biochemical techniques.The rationale for the proposed studies is that serine proteases and their receptors may participate in a signalingcascade that mediates neurodegeneration in situations where the blood brain barrier is compromised and thus mayprovide a potential therapeutic target. Because tPA is currently approved for stroke, these studies may lead to a possible adjunct therapy that enhances tPA?s beneficial effects.
| Han, Kyung-Seok; Mannaioni, Guido; Hamill, Cecily E et al. (2011) Activation of protease activated receptor 1 increases the excitability of the dentate granule neurons of hippocampus. Mol Brain 4:32 |
| Junge, Candice E; Lee, C Justin; Hubbard, Katherine B et al. (2004) Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes. Exp Neurol 188:94-103 |
| Junge, Candice E; Sugawara, Taku; Mannaioni, Guido et al. (2003) The contribution of protease-activated receptor 1 to neuronal damage caused by transient focal cerebral ischemia. Proc Natl Acad Sci U S A 100:13019-24 |
