Matthew A. Nugent, PhD
PROFESSOR OF BIOCHEMISTRY, OPHTHALMOLOGY AND BIOMEDICAL ENGINEERING
B.A., Ph.D., Brandeis University, Waltham, MA
Postdoctoral Fellowship, Massachusetts Institute of Technology, Cambridge, MA
The research in our laboratory is focused on how growth factors and the extracellular matrix interact to control mammalian cells. In particular, we are focused on how the large class of heparin-binding growth factors are regulated by heparin and heparan sulfate proteoglycans. We apply a combination of biochemical, molecular, biophysical, and computational approaches in conjunction with cell culture and animal studies to generate a systems biology view of growth factor regulation that incorporate the influence of multiple factors on one another. We apply this approach to studies aimed at understanding the details of growth factor-receptor recognition and activation, the regulation of angiogenesis, and the control of extracellular matrix turnover. Currently we are focusing on the regulation of vascular endothelial growth factor (VEGF) activity by heparan sulfate proteoglycans and fibronectin, and the consequences of inflammatory protease damage to the extracellular matrix:
1. Growth Factor Interactions with Fibronectin – In this project we are defining the central role of the extracellular matrix as a regulator of vascular growth factor activity. Specifically, we aim to identify the mechanisms and consequences of heparin/heparan sulfate-mediated catalysis of fibronectin structural rearrangements with respect to the modulation of cell function. We are also probing the growth factor-heparan sulfate network within the extracellular matrix through the use of new methods to evaluate structural patterns and activity of heparan sulfate isolated from normal and diseased tissue. We are concentrating on extracellular regulation of potent factors such as VEGF and platelet derived growth factor (PDGF) by fibronectin and heparin/heparan sulfate as a function of the mechanical and biochemical properties of the extracellular matrix. The goal of these studies is to reveal mechanisms of growth factor control that may provide insight for the design of new therapies that target growth factors to promote healthy tissue repair.
2. Inflammatory Proteases and Tissue Injury – We aim to identify the function of heparan sulfate proteoglycans (HSPGs) as regulators of proteolytic injury (particularly neutrophil elastase). We are investigating the consequences of elastase injury to the extracellular matrix on VEGF storage, release, and activity. Our previous studies have implicated proteoglycans as central mediators of elastase damage to extracellular matrix. Specifically, we have shown that HSPGs modulate growth factor storage, release, and transport within the matrix; moreover, we have also found that elastase-generated HSPG fragments feed back to inhibit elastase and that elastase leads to increased nuclear HSPGs, reduced histone acetylation, reduced tropoelastin expression, and release of VEGF fragments. We plan to expand our studies to focus on the function of released fragments of HSPGs, the specific HSPGs, syndecans 1 and 4, and VEGF. To goal of these studies is to define the consequences of protease damage on cell response to potent factors such as VEGF in order to identify new approaches to control VEGF activity.
The overriding theme to our research is to use quantitative methods to analyze complex biological processes in order to develop predictive models of living systems that can be used to probe basic mechanisms and to assist in the rational design of new therapies for human disease. Trainees in our lab benefit from a rich cross-disciplinary atmosphere as our lab is currently comprised of PhD students and postdoctoral fellows who are trained in biochemistry, biomedical engineering, chemical engineering, biology, medicine, chemistry and computer science. Thus, all members of our group are given the chance to explore research problems based on the best available approach and are not limited by existing disciplinary barriers.
Dicamillo SJ, Yang S, Panchenko MV, Toselli PA, Naggar EF, Rich CB, Stone PJ, Nugent MA, Panchenko MP. Neutrophil elastase initiated EGFR/MEK/ERK signaling counteracts the stabilizing effect of autocrine TGF-B on tropoelastin mRNA in lung fibroblasts. (2006) Am J Physiol Lung Cell Mol Physiol. 291, L232-243.
Spencer, J., Stone, P.J. and Nugent, M.A. New insights into the inhibition of human neutrophil elastase by heparin. (2006) Biochemistry 45, 9104-9120.
Mitsi, M., Hong, Z., Costello, C.E., and Nugent, M.A. Heparin-mediated conformational changes in fibronectin expose vascular endothelial growth factor binding sites. (2006) Biochemistry 45, 10319-10328.
Suki, B., Majumdar, A., Nugent, M.A., and Bates, J.H.T. In silico Modeling of Interstitial Lung Mechanics: Implications for Disease Development and Repair (2007) Drug Discovery Today: Disease Models. 4, 139-145.
Fannon, M, Forsten-Williams, K, Nugent, MA, Gregory, KJ, Chu, CL, Goerges-Wildt, AL, Panigrahy, D, Kaipainen, A, Lapp, C, Shing, Y. Sucrose Octasulfate Modulates Fibroblast Growth Factor-2 Binding, Transport and Activity: Potential for Regulation of Tumor Growth. (2008) J. Cell. Physiol. 215, 434-441.
Yang, S., Nugent, M.A., and Panchenko, M.P., EGF Antagonizes TGF-B Induced Tropoelastin Expression in Lung Fibroblasts via Stabilization of Smad Corepressor TGIF. (2008) Am J Physiol Lung Cell Mol Physiol. 295, L143-51.
Baker, A.B., Ettenson, D.S., Jonas, M., Nugent, M.A, Iozzo, R.V., and Edelman, E.R. Endothelial Cells Provide Feedback Control for Vascular Remodeling Through a Mechanosensitive Autocrine TGF-ß Signaling Pathway. (2008) Circ. Res. 103, 289-97.
Buczek-Thomas, J., Hsia, E., Rich, C.B, Foster, JA, and Nugent, M.A. Inhibition of histone acetyltransferase by heparin and heparan sulfate. (2008) J. Cell. Biochem. 105, 108-120.
Forsten-Williams, K., Chu, C.L., Fannon, M., Buczek-Thomas, J., and Nugent, M.A. Control of Growth Factor Networks by Heparan Sulfate Proteoglycans. (2008) Ann Biomed Eng 36, 2134-2148.
Mitsi, M. Forsten-Williams, K., and Nugent, M.A. A Catalytic Role for Heparin within the Extracellular Matrix. (2008) J. Biol. Chem. 283, 34796-34807.
Kurtagic, E., Jedrychowski, M., and Nugent, M.A. Neutrophil elastase cleaves VEGF to generate a VEGF fragment with altered activity. (2009) Am J Physiol Lung Cell Mol Physiol.296, L534-L546.
Ritter, M.C., Jesudason, R, Majumdar, A., Stamenovic, D., Buczek-Thomas, J., Stone, P.J., Nugent, M.A., and Suki, B. A zipper network model of the failure mechanics of extracellular matrices. (2009) Proc. Natl. Acad. Sci USA 106, 1081-1086.