UC San Diego

The p75 neurotrophin receptor (p75NTR), a tumor necrosis factor (TNF) receptor superfamily member upregulated after tissue injury, has been extensively studied as a modulator of cell death and survival within the nervous system. However, p75NTR exhibits a widespread pattern of expression during development, after injury and during a number of pathologic conditions within and outside of the nervous system. In many cases, the biological consequences of p75NTR re-expression after injury have yet to be elucidated. My dissertation research has revealed a novel function for p75NTR in the regulation of fibrinolysis after injury. Clearance of fibrin through proteolytic degradation is a critical step in extracellular matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as sciatic nerve injury, stroke, atherosclerosis, and pulmonary disease. After sciatic nerve crush injury and lipopolysaccharide (LPS) induced lung injury, we demonstrate that p75NTR blocks fibrinolysis by downregulating the serine protease, tissue Plasminogen Activator (tPA), and upregulating Plasminogen Activator Inhibitor-1 (PAI-1). Furthermore, we have identified a novel signaling pathway downstream of p75NTR in which p75NTR interacts with a specific phosphodiesterase (PDE) isoform, PDE4A5, to regulate cyclic adenosine monophosphate (cAMP) degradation and inhibit plasminogen activation. This mechanism is supported in vivo by p75NTR deficient mice, which show increased proteolysis and decreased fibrin deposition after sciatic nerve injury and lung fibrosis. p75NTR-/- mice also exhibit increased tPA activity within the cerebellum in vivo, suggesting that the regulation of cAMP by p75NTR is a general mechanism occurring within the CNS as well. In the CNS, we have demonstrated that the regulation of cAMP by p75NTR/PDE4A5 plays a role in myelin induced inhibition of neurite outgrowth in addition to its role in plasminogen activation. Our results reveal a novel pathogenic mechanism by which p75NTR promotes degradation of cAMP, inhibits fibrin clearance, and regulates tissue repair after injury