Fibroblast growth factors (GFs) play a fundamental role in development, and aberrant expression of these proteins is central to the progression of several disease states. Therefore, FGF-mediated signaling is a desirable target for therapeutic intervention. For example, enhancing FGF signaling may facilitate wound repair, whereas inhibiting FGF activity may help controlling cancer and inflammatory diseases. FGFs bind to extracellular heparin-like glycosaminoglycans (HLGAGs) and the HLGAG-FGF complex binding to its specific cognate receptor (FGFR) at the cell surface leads to FGFR oligomerization, intracellular signal transduction, and ultimately, initiation of cell proliferation or differentiation. Focusing on FGF-2 as a model system, the overall goal of this grant is to elucidate the molecular mechanism by which HLGAGs regulate FGF-2 biological activity. Our preliminary investigations suggest that FGF-2 has a tendency to self-associate and this FGF-2 oligomerization is modulated by the length and sequences of HLGAGs. Based on our preliminary findings, we hypothesize that the differential biological response of particular HLGAG sequences can be rationalized in the context of different FGF-2 dimerization/oligomerization modes they induce and stabilize. In this case, the differences between 'active' and 'inactive' HLGAGs are manifested in the mode of FGF-2 oligomerization they induce. Our preliminary studies provide a framework for an in-depth analysis of the proposed hypothesis, yielding valuable information on FGF-2 oligomerization and the role of HLGAGs in modulating FGF-2 oligomerization and how this impinges on the biological activity of FGF-2. Insight into the molecular interactions of the HLGAG-FGF system obtained from these studies will help provide leverage for new approaches to therapeutic control of FGF-mediated signal transduction in pathological situations. Further, these studies will provide a framework to investigate numerous other HLGAG-binding growth factors.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Pathobiochemistry Study Section (PBC)
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Freeman, Colette S
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Massachusetts Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
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