Laurie D. DeLeve Professor Medicine (Division of Gastrointestinal and Liver Disease) Keck School of Medicine

Education:
BSc 1976 Pre - Erasmus University of Rotterdam, The Netherlands
MD 1979 Medicine - Erasmus University of Rotterdam, The Netherlands
PhD 1988 Pharmacology - University of Toronto, Canada

Postdoctoral Research Fellowship:
1980 - 1981 University of Toronto, Canada

Started at USC: 1990

Research Topics: Toxicology, Cancer Treatment, Stem Cell Biology

Research Description

The overriding theme in my research is to examine basic mechanisms underlying liver disease, always with the hope that this will lead to new therapeutic strategies.

Our laboratory is pursuing two main areas of investigation. One research focus is on hepatic venoocclusive disease (or sinusoidal obstruction syndrome) as a model of liver injury that originates within the hepatic microcirculation. We have demonstrated that this disease is initiated by damage to the sinusoidal endothelial cells, the cells that line the hepatic microcirculation, and we have elucidated various steps in the biochemical pathways that lead to this injury. Our studies have demonstrated that sinusoidal endothelial cells are repaired by adult stem cells from the bone marrow and that repair by the bone marrow is a determinant of the severity of injury. Studies are underway to examine which bone marrow lineage sinusoidal endothelial cells are derived from and to elucidate the pathways that convert a circulating bone marrow-derived progenitor into a cell with the phenotypic characteristics of a sinusoidal endothelial cell.

The second area of investigation focuses on "capillarization" of the liver. Hepatic sinusoidal endothelial cells have a unique phenotype with open fenestration ("holes" with a diameter of 150 micron) that are clustered in so-called sieve plates and without an organized basement membrane. Capillarization is a pathologic state in which hepatic sinusoidal endothelial cells revert to non-fenestrated endothelial cells with an organized basement membrane, a phenotype similar to that seen in much of the capillary bed. Capillarization occurs in aging and is seen prior to fibrotic liver disease. Sinusoidal endothelial cell fenestrae form a "sieve" that determines the size of chylomicron remnant clearance by the liver and age-related capillarization with loss of fenestration may be of importance for hyperlipidemia and atherosclerosis. We are currently investigating whether capillarization prior to fibrotic disease may be a permissive step in the fibrotic process. Our studies have identified paracrine and autocrine factors that regulate the sinusoidal endothelial cell phenotype in normal liver and studies in progress are characterizing the dysregulation of phenotypic control in models of liver disease.