Department of Regenerative Medicine and Cell biology
W. Scott Argraves,
Room 653, Basic Science
BS Biological Sciences Univ. of Connecticut 1978
PhD Cell-Developmental Biology Univ. of Connecticut 1985
Postdoctoral Fellow at La Jolla Cancer Research Foundation 1988
One goal of my research is to contribute to an understanding of the molecular basis for the function of extracellular matrix (ECM) as a regulator of cellular behavior in normal and disease processes. My work has focused on determining the structure and patterns of expression of various ECM proteins, characterizing the intermolecular interactions of ECM proteins (particularly those responsible for mediating assembly of fibers and basement membranes), identifying receptors for ECM proteins and characterizing signaling events that such receptors elicit during development and disease.
Another major focus of my research is lipoprotein metabolism involving members of the low density lipoprotein (LDL) receptor family. One family member that I have focused on is LRP-2/megalin which functions in tissues such as the kidney, lung, brain, intestine and yolk sac to regulate the extracellular accumulation of an array of proteins. For example, LRP-2/megalin mediates endocytosis and lysosomal degradation of LDL, apolipoprotein J, lipoprotein lipase, seminal vesicle secretory protein-II, uPA-PAI-1 and a number of other ligands. The vital role that LRP-2/megalin plays is underscored by the finding that mice deficient in this receptor have gross developmental abnormalities and do not survive. During the course of our LRP-2/megalin research we discovered a LRP-2/megalin co-receptor called cubilin. We found that cubilin functions in conjunction with LRP-2/megalin to mediate endocytosis of high density lipoproteins (HDL) leading to the catabolism of HDL via lysosomal degradation. Work in the lab is currently directed toward determining the physiological significance of cubilin/megalin-mediated HDL uptake in the embryo and adult. We have generated mice deficient in cubilin and established the critical role of cubilin in early embryogenesis. We are now developing a mouse strain carrying a floxed cubilin allele that will enable us to generate animals conditionally deficient in cubilin expression. This will allow us to determine the role of cubilin expression in adult tissues including the intestine and kidney and the impact of absence these proteins on plasma HDL homeostasis.