: Following injury, there is an immediate accumulation of platelets on the injured surface and a significant associated stress response in the underlying smooth muscle cells. LPA is produced in platelets from phosphatidic acid by phospholipase A2 and plays a role in stimulating cell proliferation and migration during vessel wall healing acting in concert with other platelet derived mediators. For this reason we are focussing on G-protein coupled cell signaling and transduction pathways. LPA binds to specific LPA receptors (LPA 2, 4, 6 and 7) and induces G-protein coupled signaling leading to smooth muscle cell proliferation. We have identified a role for p38MAPK activation in smooth muscle cell proliferation in response to LPA. The central hypothesis we plan to test is that LPA acting through specific LPA receptors activates large Galphai subunits leading to activation of the small G-proteins (ras, rac and rho), which induces p38MAPK phosphorylation and smooth muscle cell proliferation. The following specific aims will be addressed in the present proposal to test this hypothesis: 1/ To characterize the heterotrimeric 0-protein coupled signal transduction leading to p38MAPK activation. 2/ To elucidate the role of small G-protein pathways (ras, rac and rho) linked to activation p38MPK. 3/ To examine upstream kinase activity during p38MAPK activation by LPA. The stress kinases in smooth muscle cells are important in the response to injury and this study will begin to define of the complex activation pathways involved in stress kinase activity and will allow the development of strategies targeting the stress component in response to injury.
|Tanski, William J; Nicholl, Suzanne M; Kim, Dong et al. (2005) Sphingosine-1-phosphate-induced smooth muscle cell migration involves the mammalian target of rapamycin. J Vasc Surg 41:91-8|
|Tanski, William John; Roztocil, Elisa; Hemady, Eric A et al. (2004) Role of Galphaq in smooth muscle cell proliferation. J Vasc Surg 39:639-44|
|Tanski, William J; Fegley, Allison J; Roztocil, Elisa et al. (2004) Domain-dependent action of urokinase on smooth muscle cell responses. J Vasc Surg 39:214-22|
|Fegley, Allison J; Tanski, William J; Roztocil, Elisa et al. (2003) Sphingosine-1-phosphate stimulates smooth muscle cell migration through galpha(i)- and pi3-kinase-dependent p38(MAPK) activation. J Surg Res 113:32-41|
|Tanski, William; Roztocil, Elisa; Davies, Mark G (2002) Sphingosine-1-phosphate induces G(alphai)-coupled, PI3K/ras-dependent smooth muscle cell migration. J Surg Res 108:98-106|