Retinal vascular diseases represent some of the most significant causes of visual loss in the United States, and include diabetic retinopathy, retinopathy of prematurity, and the neovascular subtype of age-related macular degeneration. The retinal vasculature is directly observable through the ophthalmoscope, and, as a consequence, there is a large body of data on its appearance in the context of ocular disease. The signaling systems that control retinal vascular development and that participate in the pathobiology of retinal vascular disease are the subject of intense interest. One such signaling system is the Norrin-Frizzled4 ligand-receptor system. In humans and mice, mutations in the genes encoding either the ligand Norrin, the receptor Frizzled4, or the coreceptor Lrp5 cause pathologic hypovascularization of the retina, with compensatory neovascularization. The present application proposes to address the following fundamental questions related to this signaling system. (1) Which cells are responsible for producing Norrin and which cells use Frizzled4 to respond to Norrin? (2) Are there Norrin receptors in addition to Frizzled4? (3) If, as seems likely, Norrin acts directly on endothelial cells, does it promote proliferation, direct cell motility, or induce other responses? (4) Is the Norrin-Frizzled4 signaling system active in the adult retina, and can it modify the natural history or severity of mouse models of retinopathy of prematurity or choroidal neovascularization? (5) What is the structural basis for Norrin's ability to distinguish Frizzled4 from the other nine mammalian Frizzleds? (6) How does Norrin activate conformational alterations in Frizzled4 and its co-receptor Lrp5? Answers to these questions will shed light on the role of Norrin-Frizzled4 signaling in the context of normal and pathologic retinal vascular biology. ? ? ?
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