Biochemical Journal Poster Prize winner

Brian Connolly

Since completing his B.S. at Cornell University in 2008, Brian Connolly performed research on the plasminogen activation system in the laboratory of Thomas Bugge, NIH. His work has focused on the urokinase type plasminogen activator (uPA) and its receptor, the uPAR (uPA receptor). uPAR has emerged as a potential regulator of cell adhesion, cell migration, proliferation, differentiation and cell survival in multiple contexts. Elucidation of the specific role of uPA binding to uPAR, however, is complicated because uPA has important physiological functions that are independent of binding to uPAR and because uPAR engages multiple ligands. By introducing four amino acid substitutions into the growth factor domain of uPA, we developed a mouse strain (Plau^GFDhu/GFDhu) where the interaction between endogenous uPA and uPAR is abrogated, while other functions of both the protease and its receptor are retained. Analysis of Plau^GFDhu/GFDhu mice revealed an unanticipated role of the uPA-uPAR interaction in suppressing fibrin-associated inflammation, while leukocyte recruitment and tissue regeneration were unaffected by the loss of uPA binding to uPAR. This study identifies a role of the uPA-uPAR interaction in cell-associated fibrinolysis critical for suppression of fibrin accumulation and fibrin-associated inflammation, and provides a valuable model for further exploration of this multifunctional receptor.