The ISFP Prize Lecture 2010 "From PAI-1 to PDGF in the brain, a series of fortunate events" will be presented by Daniel A. Lawrence Ph.D., University of Michigan, Ann Arbor, MI, USA.
Plenary session 11, Friday, August 27, 10.30-11.15 am.

Daniel A. Lawrence, Ph.D. is Professor, Internal Medicine Department, University of Michigan, Ann Arbor, MI. His research interests are thrombosis and vascular biology. The Lawrence lab at the Univerity of Michigan studies the role of proteases and their inhibitors in health and disease. Primary areas of interest focus on the vascular biology of stroke and the development of atherosclerosis.

For more information on Dr. Lawrence and his research activities, please click here.

Lecture abstract: From PAI-1 to PDGF in the brain, a series of fortunate events

Fibrinolysis has been studied for well over 100 years, and the enzymatic components of the plasminogen activator (PA) system have been known since the 1940’s. However, it was only in the 1990’s that it began to be appreciated that plasminogen activators might be acting on substrates other than plasminogen, and that their regulation of physiologic systems may occur through pathways other than fibrinolysis. Our work has focused on understanding the non-traditional roles of plasminogen activators and their inhibitors in normal and pathologic physiology. Studies have included characterization of the inhibitory mechanism of Serpins and demonstration of how this mechanism provides conformational control of both protease and non-protease ligand interactions, which in-turn regulate complex cellular and physiologic functions. Studies have also investigated plasminogen independent roles of PAs and their inhibitors in the central nervous system (CNS). This work has demonstrated that tissue-type PA (tPA) can directly regulate the blood brain barrier (BBB) through interactions with the neurovascular unit (NVU). In vivo results indicate that this occurs through tPA-mediated activation of latent platelet-derived growth factor CC (PDGF-CC). Specific proteolysis of PDGF-CC by tPA generates active PDGF-CC capable of triggering PDGF receptor  (PDGFR) signaling in perivascular astrocytes within the NVU, which in-turn controls BBB permeability. The regulation of BBB integrity after stroke plays a critical role in stroke progression and in hemorrhagic transformation. Understanding this pathway may hold the key to developing better treatments for stroke and potentially other CNS disorders where BBB integrity is disrupted.