VEGF-Extracellular Matrix Interactions in Choroidal Neovascularization
Dr. Matthew Nugent and colleagues are seeking to determine if a new biochemical process that they have discovered plays a critical role in causing the abnormal growth of blood vessels into the retina in wet AMD. VEGF is increased in wet AMD, and inhibitors of VEGF have been shown to be somewhat effective in treating this disease. Nugent recently discovered that a complex sugar called heparan sulfate, when made by cells grown in low oxygen, can modify the association of VEGF with a protein called fibronectin, which is part of the surrounding cell-support meshwork. Preliminary data indicate that VEGF becomes activated upon association with fibronectin by presenting it to its binding partners and protecting it from natural inhibitors. This may lead to enhanced recruitment of blood vessel cells. Current therapies are designed to bind free VEGF or VEGF partners to inhibit the activity. Thus, VEGF associated with fibronectin may be shielded from these therapies, which may be part of the reason that current treatments are only partially effective.
Nugent's project aims to explore how this new process (VEGF binding to fibronectin) may cause abnormal blood vessel growth and to determine if targeting this new interaction may fully inhibit growth beyond that observed with current therapies. Furthermore, the idea that heparan sulfate may control this process is novel and may represent a newly discovered biological mechanism that tissues use to locally control the activity of potent factors such as VEGF. At the end of this study, Nugent will have a better understanding of the structure and activity requirements for heparan sulfate to modify fibronectin, which will provide insight into designing new complex sugars to antagonize this process.
About the Researcher
Dr. Matthew Nugent is a Professor of Biochemistry, Biomedical Engineering and Ophthalmology at the Boston University School of Medicine and is Director of Research for the Department of Ophthalmology. He received his B.A. and Ph.D. degrees in biochemistry from Brandeis University in Waltham, MA, in 1983 and 1990 respectively. He did postdoctoral research at MIT in Boston, MA, from 1989 to1992 under the direction of professors Robert Langer and Elazer Edelman in the Department of Chemical Engineering and in the Harvard-MIT Division of Health Sciences and Technology. Since joining the faculty at Boston University in 1993, the research in his laboratory has aimed to understand the mechanisms underlying the response of various tissues to injury and disease with a particular emphasis on the role of the extracellular matrix, growth factors, and complex polysaccharides. His research interests include the regulation of angiogenesis by growth factors (FGF, VEGF, and TGFbeta) and heparan sulfate proteoglycans, and the involvement of growth factors and proteoglycans in the pathology of vascular disease and ocular disorders. He is also involved in the design and use of polymer-based controlled drug delivery systems, tissue engineering, and the development of computational models of dynamic biological processes. His research has led to more than 95 peer-reviewed papers, 4 patents, and more than 150 invited lectures and published abstracts.
Nugent is a reviewer for various journals, is a member of the Biochemical Journal editorial board, has served on several NIH and private foundation grant review panels, and has served as a consultant for a number of biotechnology and pharmaceutical companies. He is a member of the Biochemical Society, ARVO, ASBMB, ASCB, and AAAS.
First published on: July 10, 2012
Last modified on: June 13, 2012