Matthew A. Nugent
Professor of Biochemistry
Departments of Biochemistry, Ophthalmology, and Biomedical Engineering
Boston University School of Medicine
Silvio Conte Building, K420
72 E. Concord Street
Boston, MA 02118
Phone: 617-638-4169
Fax: 617-638-5339
Email: nugent@biochem.bumc.bu.edu
Education
B.A., Brandeis University, Waltham, MA
Ph.D., Brandeis University, Waltham, MA
Research Interest
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 involvement of these processes in cardiovascular disease and chronic obstructive pulmonary disease.
1. Cardiovascular disease is the number one cause of death in the United Sates. Research has focused on a variety of factors involved in these complex disease processes. In particular, neointimal expansion in atherosclerotic blood vessels and during restenosis is characterized by a series of events that reflect an attempt of the resident vascular cells to repair the dysfunctional blood vessel wall. However, in disease these same processes may also contribute to a cascading propagation of the “injured/inflamed” state such that the response contributes to continued vascular dysfunction. At the center of this stimulus-response network is the extracellular matrix, which both regulates and is regulated by the resident cells in the blood vessel wall. 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 vascular cell function. We are also probing the growth factor-heparan sulfate network within the blood vessel wall through the use of new methods to evaluate structural patterns and activity of heparan sulfate isolated from normal and atherosclerotic arteries. We are concentrating on extracellular regulation of potent factors such as vascular endothelial growth factor (VEGF) by fibronectin and heparin/heparan sulfate as a function of the mechanical and biochemical properties of the extracellular matrix.
2. Chronic Obstructive Pulmonary Disease, which includes emphysema, is the fourth leading cause of death in the United States, accounting for more than 120,000 deaths in 2002. To develop effective therapies for this “quiet killer” a more complete understanding of the underlying cellular and molecular causes is required. In this project, we aim to identify new critical components of how the lung responds, appropriately and inappropriately, to a specific type of injury (elastolysis) so that this information might provide insight toward the development of therapies to assist lung repair and avoid disease. In particular, we aim to identify the function of heparan sulfate proteoglycans (HSPGs) as regulators of elastolysis and modulators of the cellular response to injury. In addition, we will investigate the consequences of elastase injury to the extracellular matrix on vascular endothelial growth factor (VEGF) storage, release, and activity. Our previous studies have implicated proteoglycans as central mediators of elastase damage to pulmonary cells and 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.
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.
Representative Publications
Goerges, A.L., and Nugent, M.A. Regulation of vascular endothelial growth factor binding and activity by extracellular pH. (2003) J. Biol. Chem. 278, 19518-25.
Fannon, M., Forsten-Williams, K.E., Dowd, C.J., Freedman, D.A., Folkman, J., and Nugent, M.A. Binding inhibition of angiogenic factors by heparan sulfate proteoglycans in aqueous humor: Potential mechanism for maintainance of an avascular environment. (2003) FASEB J. 17, 902-4.
Izvolsky KI, Zhong L, Wei L, Yu Q, Nugent MA, Cardoso WV. Heparan sulfates expressed in the distal lung are required for FGF10 branching to the epithelium and for airway branching. (2003) Am. J. Physiol Lung Cell Mol. Physiol. 285:L838-46.
Rich CB, Carreras I, Lucey EC, Jaworski JA, Buczek-Thomas JA, Nugent MA, Stone P, Foster JA. Transcriptional Regulation of Pulmonary Elastin Gene Expression In Elastase-Induced Injury. (2003) Am. J. Physiol Lung Cell Mol. Physiol. 285, L354-62.
Liu J, Rich CB, Buczek-Thomas JA, Nugent MA, Panchenko MP, Foster JA. Heparin-binding EGF-like growth factor regulates elastin and FGF-2 expression in pulmonary fibroblasts. (2003) Am J Physiol Lung Cell Mol Physiol. 285:L1106-15.
Chua CC, Rahimi N, Forsten-Williams K, Nugent MA. Heparan sulfate proteoglycans function as receptors for fibroblast growth factor-2 activation of extracellular signal-regulated kinases 1 and 2. (2004) Circ Res. 94:316-23.
Chu CL, Buczek-Thomas JA, Nugent MA. Heparan sulphate proteoglycans modulate fibroblast growth factor-2 binding through a lipid raft-mediated mechanism. (2004) Biochem J. 379:331-41.
Goerges AL, Nugent MA. pH Regulates Vascular Endothelial Growth Factor Binding to Fibronectin: A Mechanism for control of extracellular storage and release. (2004) J Biol Chem. 279:2307-15.
Buczek-Thomas JA, Lucey EC, Stone PJ, Chu CL, Rich CB, Carreras I, Goldstein RH, Foster JA, Nugent MA. Elastase mediates the release of growth factors from lung in vivo. (2004) Am J Respir Cell Mol Biol. 31:344-50.
Chu, CL, Goerges, AL, Nugent, MA. Identification of common and specific growth factor binding sites in heparan sulfate proteoglycans. (2005) Biochemistry 44, 12203-13.
Gopalakrishnan, M., Forsten-Williams, K., Nugent, M. A., and Tauber, U. C. (2005) Effects of receptor clustering on ligand dissociation kinetics: theory and simulations, Biophys J 89, 3686-700.
Forsten-Williams, K., Chua, C. C., and Nugent, M. A. (2005) The kinetics of FGF-2 binding to heparan sulfate proteoglycans and MAP kinase signaling, J Theor Biol 233, 483-99.
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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-β 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-β 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.
