In a mouse model of ROP, up-regulation of vascular endothelial growth factor (VEGF) is important in vaso-proliferation and down-regulation of VEGF is important in vaso-obliteration. Inhibition of VEGF inhibits retinal neovascularization. However, total systemic inhibition of VEGF may cause exacerbation of the first phase of ROP and may pose problems with fetal development. Therefore, alternative pathways that control ROP will be important. The applicants have shown that indirect suppression of serum IGF-1 through growth hormone (GH) suppression inhibits retinal neovascularization. These results predict that direct inhibition of IGF-1 will suppress neovascularization and that blocking IGF-1 receptors to block local as well as serum IGF-1 would be more potent than inhibiting GH. Moreover, partial inhibition of both VEGF and serum IGF-1 in combination might be more effective and safer than complete inhibition of either one alone. The overall goal of this proposal is to investigate the therapeutic potential of manipulation of VEGF and IGF-1 and the potential of combination therapy. Specific aim 1 uses an IGF-1 agonist and IGF-1 antagonist in a mouse model of ROP to evaluate the therapeutic potential of IGF-1 manipulation in the vaso-proliferative and vaso-obliterative phases of ROP. Parallel studies in vitro will be carried out on retinal endothelial cells (RECs). Oxygen regulation of IGF-1, receptor and binding proteins will be done in vivo and in vitro. Specific aim 2 will evaluate the potential of combined control of VEGF and IGF-1 in ROP both in vivo and in vitro to determine the interaction between VEGF and IGF-1 control of endothelial cell growth and survival.