Welcome to the Argraves Laboratory
Welcome to the laboratory of W. Scott Argraves in the Department of Regenerative Medicine and Cell Biology at the Medical University of South Carolina in Charleston, South Carolina.
A major emphasis of research in the Argraves Laboratory is extracellular matrix (ECM) biology. Much of what is known about cellular behavior such as growth, movement and differentiation can be related to cellular interaction with components of the ECM. ECM can be viewed simplistically as a three dimensional network of interacting molecules that surrounds cells. The composition and organization of ECM in tissues is variable depending on regional dynamics of protein and carbohydrate biosynthesis, matrix assembly and turnover. The interaction of cells with these variable three-dimensional ECM networks elicits differential patterns of gene expression and cellular behaviors that are critical to processes such as cellular growth, tissue morphogenesis, wound repair and maintenance of specialized phenotype. A goal of research in the Argraves Laboratory is to contribute to an understanding of the molecular basis for the function of ECM as an effector of cellular behavior in normal and disease processes. To accomplish this goal, the work focuses 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.
Currently, the major aim of ECM research in the Argraves Laboratory is to determine the function of fibulin-1, an ECM protein that Dr. Argraves discovered. This research objective has been advanced by our development of a novel mouse model of fibulin-1 deficiency. Fibulin-1 deficiency leads to embryonic lethality accompanied by cardiac outflow tract and septal defects, hypoplastic pharyngeal glands and under mineralized, reduced sized skull bones. Collectively, these defects are consistent with the spectrum of anomalies associated with DiGeorge syndrome (Velo-Cardio-Facial Syndrome), a disorder that occurs with a frequency of 1:4000 human births. DiGeorge Syndrome is a neurocristopathy, since neural crest cell abnormalities are believed to underlie DiGeorge pathogenesis. Recent findings indicate that fibulin-1 deficiency leads to neural crest cell abnormalities that include defects in the guidance and survival of cranial neural crest cells (Cooley et al., 2008).
Another major focus of research in the laboratory is the study of lipoprotein receptors. In particular, we are focused on understanding the structure and function of a member of the low density lipoprotein (LDL) receptor family referred to megalin (also known as LRP-2). Megalin can be considered a scavenger that functions in tissues such as the kidney, lung, brain and yolk sac to regulate the extracellular accumulation of an array of proteins. For example, megalin mediates endocytosis and lysosomal degradation of many ligands including the vitamin-carrier proteins retinal binding protein (RBP), vitamin D-binding protein, and transcobalamin. The vital role that megalin plays is underscored by the finding that transgenic mouse embryos, deficient in this receptor have neurodevelopmental abnormalities. Importantly, we have discovered that megalin is a receptor for sonic hedgehog (McCarthy et al., 2002) a morphogen important for neurodevelopment. Studies are ongoing to determine the significance of megalin to sonic hedgehog-dependent patterning of the embryonic brain.
Investigators in the Argraves Laboratory have discovered that cubilin is a receptor for high density lipoproteins (HDL). Cubilin and megalin work in conjunction to mediate endocytosis of HDL leading to its catabolism via lysosomal degradation in tissues such as the kidney and yolk sac. Workers in the Argraves laboratory have developed a novel mouse strain having a targeted deletion of the cubilin gene (Smith et al., 2006). Embryos deficient in cubilin arrest early in development and display vascular and yolk sac morphological defects as well as a failure to form somites. Work in the lab is currently directed toward determining the morphogenic pathways that are disrupted in cubilin-deficient embryos. Importantly, embryos deficient in cubilin fail to take up maternal derived HDL.
W. Scott Argraves earned a Ph.D. in cellular and developmental biology at the University of Connecticut in 1985, where he studied extracellular matrix biology with Paul F. Goetinck. He subsequently undertook postdoctoral studies in integrin based cell adhesion biology with Erkki Ruoslahti at the La Jolla Cancer Research Foundation, now The Burnham Institute for Medical Research, La Jolla, CA. He launched his independent research career at the American Red Cross, J.H. Holland Laboratory in Rockville, MD where he was a senior scientist in the Department of Biochemistry. In 1995, he moved to the Medical University of South Carolina in Charleston and established a research laboratory (http://argraves-lab.musc.edu) in the Department of Cell Biology and Anatomy (recently reorganized into the Department of Regenerative Medicine and Cell Biology). In 2001 he was promoted to Professor and in 2008 Associate Chair for Research. Dr. Argraves’ research interests have primarily focused on extracellular matrix and receptor biology, with special emphasis on cardiovascular development and disease.