Department of Regenerative Medicine and Cell biology

W. Scott Argraves

W. Scott Argraves, Ph.D.
Professor

Director, MUSC Proteogenomics Facility
Director, South Carolina INBRE Bioinformatics Core
Associate Chair of Research
Adjunct Professor of Bioengineering, Clemson University

Room 653, Basic Science Building
Office: (843) 792-5482
Lab Phone: (843( 792-5483


Email: argraves@musc.edu

Argraves Laboratory Website

Education:

BS Biological Sciences Univ. of Connecticut 1978
PhD Cell-Developmental Biology Univ. of Connecticut 1985
Postdoctoral Fellow at La Jolla Cancer Research Foundation 1988

Research Interests:

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.

One aspect of my ECM work centers on investigating the function of an ECM protein that I discovered and named fibulin-1. Our findings from targeted gene inactivation studies in mice reveal that fibulin-1 is required for normal development of the cardiac outflow tract (OFT), pharyngeal glands, cranial nerves and bones of the skull. The developmental anomalies displayed by mice deficient in fibulin-1 recapitulate many of the phenotypes associated with 22q11 deletion/DiGeorge syndrome (DGS), which occurs with a frequency of 1:4000 human births. The spectrum of malformations observed in fibulin-1 nulls is consistent with fibulin-1 playing a critical role in the migration and survival of cranial neural crest cells (NCCs), particularly those that derive from the portion of the neural tube that includes rhombomere 4 through the third somite. These NCCs contribute to cranial nerves, thymus, thyroid and parathyroid glands and facilitate septation of the common OFT into aortic and pulmonary arteries. They also migrate into the secondary heart field (SHF), which contributes the OFT myocardium critical for normal alignment of the two outflow vessels. The similarity in phenotypes between fibulin-1-deficient mice and DGS humans suggests that fibulin-1, although located outside of the 22q11 deletion region, is a modifier of the pathway that is dysfunctional in DGS.

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.

Recent Publications:

  1. Aseem, O., J. L. Barth, S. C. Klatt, B. T. Smith and W. S. Argraves. "Cubilin Expression Is Monoallelic and Epigenetically Augmented Via Ppars." BMC Genomics 14, (2013): 405 [PMID: 23773363]
  2. Hansen, M. L., J. S. Dahl, W. S. Argraves, A. Irmukhamedov and L. M. Rasmussen. "Aortic Valve Stenosis and Atrial Fibrillation Influence Plasma Fibulin-1 Levels in Patients Treated with Coronary Bypass Surgery." Cardiology 126, no. 3 (2013): 202-206 [PMID: 24051963]
  3. Laugesen, E., P. Hoyem, J. S. Christiansen, S. T. Knudsen, K. W. Hansen, W. S. Argraves, T. K. Hansen, P. L. Poulsen and L. M. Rasmussen. "Plasma Levels of the Arterial Wall Protein Fibulin-1 Are Associated with Carotid-Femoral Pulse Wave Velocity: A Cross-Sectional Study." Cardiovasc Diabetol 12, no. 1 (2013): 107 [PMID: 23866070]
  4. Mainous, A. G., 3rd, R. U. Wright, M. M. Hulihan, W. O. Twal, C. E. McLaren, V. A. Diaz, G. D. McLaren, W. S. Argraves and A. M. Grant. "Telomere Length and Elevated Iron: The Influence of Phenotype and Hfe Genotype." Am J Hematol 88, no. 6 (2013): 492-6 [PMID: 23512844]
  5. Scholze, A., E. M. Bladbjerg, J. J. Sidelmann, A. C. Diederichsen, H. Mickley, M. Nybo, W. S. Argraves, P. Marckmann and L. M. Rasmussen. "Plasma Concentrations of Extracellular Matrix Protein Fibulin-1 Are Related to Cardiovascular Risk Markers in Chronic Kidney Disease and Diabetes." Cardiovasc Diabetol 12, (2013): 6 [PMID: 23294625]
  6. Sproul, E. P. and W. S. Argraves. "A Cytokine Axis Regulates Elastin Formation and Degradation." Matrix Biol 32, no. 2 (2013): 86-94 [PMID: 23160093]
  7. Twal, W. O., S. C. Klatt, K. Harikrishnan, E. Gerges, M. A. Cooley, T. C. Trusk, B. Zhou, M. G. Gabr, T. Shazly, S. M. Lessner, R. R. Markwald and W. S. Argraves. "Cellularized Microcarriers as Adhesive Building Blocks for Fabrication of Tubular Tissue Constructs." Ann Biomed Eng, (2013) [PMID: 23943070]
  8. Cooley, M. A., V. M. Fresco, M. E. Dorlon, W. O. Twal, N. V. Lee, J. L. Barth, C. B. Kern, M. L. Iruela-Arispe and W. S. Argraves. "Fibulin-1 Is Required During Cardiac Ventricular Morphogenesis for Versican Cleavage, Suppression of Erbb2 and Erk1/2 Activation, and to Attenuate Trabecular Cardiomyocyte Proliferation." Dev Dyn 241, no. 2 (2012): 303-14 [PMID: 22183742]
  9. Krejci, E., Z. Pesevski, A. C. DeAlmeida, M. Mrug, V. M. Fresco, W. S. Argraves, J. L. Barth, X. Cui and D. Sedmera. "Microarray Analysis of Normal and Abnormal Chick Ventricular Myocardial Development." Physiol Res 61 Suppl 1, (2012): S137-44 [PMID: 22827870]
  10. Kruger, R., R. Schutte, H. W. Huisman, W. S. Argraves, L. M. Rasmussen, M. H. Olsen and A. E. Schutte. "Nt-Probnp Is Associated with Fibulin-1 in Africans: The Safreic Study." Atherosclerosis 222, no. 1 (2012): 216-21 [PMID: 22349089]
  11. Wilkerson, B. A., G. D. Grass, S. B. Wing, W. S. Argraves and K. M. Argraves. "Sphingosine 1-Phosphate (S1p) Carrier-Dependent Regulation of Endothelial Barrier: High Density Lipoprotein (Hdl)-S1p Prolongs Endothelial Barrier Enhancement as Compared with Albumin-S1p Via Effects on Levels, Trafficking, and Signaling of S1p1." J Biol Chem 287, no. 53 (2012): 44645-53 [PMID: 23135269]
  12. Zyblewski, S. C., W. S. Argraves, E. M. Graham, E. H. Slate, A. M. Atz, S. M. Bradley, T. C. McQuinn, B. A. Wilkerson, S. B. Wing and K. M. Argraves. "Reduction in Postoperative High-Density Lipoprotein Cholesterol Levels in Children Undergoing the Fontan Operation." Pediatr Cardiol 33, no. 7 (2012): 1154-9 [PMID: 22411716]
  13. Argraves, K. M., A. A. Sethi, P. J. Gazzolo, B. A. Wilkerson, A. T. Remaley, A. Tybjaerg-Hansen, B. G. Nordestgaard, S. D. Yeatts, K. S. Nicholas, J. L. Barth and W. S. Argraves. "S1p, Dihydro-S1p and C24:1-Ceramide Levels in the Hdl-Containing Fraction of Serum Inversely Correlate with Occurrence of Ischemic Heart Disease." Lipids Health Dis 10, (2011): 70 [PMID: 21554699]
  14. Cangemi, C., V. Skov, M. K. Poulsen, J. Funder, W. O. Twal, M. A. Gall, V. Hjortdal, M. L. Jespersen, T. A. Kruse, J. Aagard, H. H. Parving, S. Knudsen, P. F. Hoilund-Carlsen, P. Rossing, J. E. Henriksen, W. S. Argraves and L. M. Rasmussen. "Fibulin-1 Is a Marker for Arterial Extracellular Matrix Alterations in Type 2 Diabetes." Clin Chem 57, no. 11 (2011): 1556-65 [PMID: 21926180]
  15. Argraves, K. M., B. A. Wilkerson and W. S. Argraves. "Sphingosine-1-Phosphate Signaling in Vasculogenesis and Angiogenesis." World J Biol Chem 1, no. 10 (2010): 291-7 [PMID: 21537462]
  16. Barth, J. L., C. D. Clark, V. M. Fresco, E. P. Knoll, B. Lee, W. S. Argraves and K. H. Lee. "Jarid2 Is among a Set of Genes Differentially Regulated by Nkx2.5 During Outflow Tract Morphogenesis." Dev Dyn 239, no. 7 (2010): 2024-33 [PMID: 20549724]
  17. Fleming, P. A., W. S. Argraves, C. Gentile, A. Neagu, G. Forgacs and C. J. Drake. "Fusion of Uniluminal Vascular Spheroids: A Model for Assembly of Blood Vessels." Dev Dyn 239, no. 2 (2010): 398-406 [PMID: 19918756]
  18. Jani, S. D., G. L. Argraves, J. L. Barth and W. S. Argraves. "Genemesh: A Web-Based Microarray Analysis Tool for Relating Differentially Expressed Genes to Mesh Terms." BMC Bioinformatics 11, (2010): 166 [PMID: 20359363]
  19. Kern, C. B., A. Wessels, J. McGarity, L. J. Dixon, E. Alston, W. S. Argraves, D. Geeting, C. M. Nelson, D. R. Menick and S. S. Apte. "Reduced Versican Cleavage Due to Adamts9 Haploinsufficiency Is Associated with Cardiac and Aortic Anomalies." Matrix Biol 29, no. 4 (2010): 304-16 [PMID: 20096780]
  20. Szabo, A., R. Unnep, E. Mehes, W. O. Twal, W. S. Argraves, Y. Cao and A. Czirok. "Collective Cell Motion in Endothelial Monolayers." Phys Biol 7, no. 4 (2010): 046007 [PMID: 21076204]

 

 

 

 

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