Proliferative vitreoretinal diseases lead to severe visual loss and blindness as a consequence of uncontrolled cellular proliferation, retinal detachment, and subsequent neuronal cell injury. These diseases are regulated by local growth factors and their modulators. One leading candidate is basic fibroblast growth factor (FGF-2). This protein is a potent mitogen which is elevated in the vitreous fluids of patients with proliferative diabetic retinopathy (PDR) and proliferative vitreoretinopathy (PVR). Understanding the mechanisms which regulate the biological activity of FGF-2 is fundamental to developing novel approaches to controlling intraocular proliferation. This proposal focuses on the role of high affinity FGF receptors in regulating the biological activity of FGF-2 in vivo. Recently, we discovered a new potential regulatory mechanism for controlling the biological properties of FGF: the presence of soluble FGF receptors. These proteins are potential FGF antagonists and are present in vitreous fluid. In light of their ability to sequester and bind FGF-2, they may explain the longstanding dichotomies between the potent activity of FGF in vitro, its wide distribution in tissues, and the highly controlled activity of FGF-2 in vivo. This proposal is focused on the hypothesis that the mitogenic activity of FGF-2 in vivo is regulated by soluble FGF receptors. We have designed this application to purse fundamental basic science questions on the regulation of growth factor activity in a disease-oriented approach. To investigate the hypothesis, we have selected four Specific Aims. We will first identify the cellular source of the soluble FGF receptors in vitreous fluid. This will be performed by analyzing the cellular distribution of soluble FGF receptors by immunohistochemistry and in situ hybridization. To complement these studies, we will identify which cells derived from the posterior pole release the soluble receptors in vitro. These cells will then be used to examine the conditions which regulate the release of soluble FGF receptors in vitro. We will determine whether the soluble FGF receptors potentiate or inhibit the mitogenic activity of FGF-2 and uncover what mechanisms are associated with these effects. We will also examine the clinical relevance of the soluble receptors in vitreoretinal disease by correlating the levels of the soluble FGF receptors in vitreous specimens with the levels of FGF-2 and the extent of intraocular proliferation. These studies will examine the critical balance between stimulators of intraocular proliferation and the proteins which modulate the mitogenic activity of growth factors. Understanding the biological activity of the soluble FGF receptors in vitreous fluid may lead to a paradigm shift in our understanding of the regulation of growth factor activity and could thus lead to a novel form of treatment to control the biological activity of FGF in vivo.
| Hanneken, A (2001) Structural characterization of the circulating soluble FGF receptors reveals multiple isoforms generated by secretion and ectodomain shedding. FEBS Lett 489:176-81 |
