Retinopathy of prematurity (ROP) is a blinding disease of premature infants. Current ablative treatment is only partially effective in preventing vision loss. A medical treatment is essential. ROP occurs in 2 phases. Loss of vessels and cessation of vessel growth causes retinal hypoxia (phase I), which leads to phase II neovascularization (NV). Our overall goal is to understand the mechanism of ROP and to find therapies to treat the disease in both phases. Inhibition of IGF-1 in phase II can control NV. Paradoxically, low IGF-1 after birth is a very strong risk factor for the development of ROP since IGF-1 is required to prevent vessel loss. Thus, a potentially serious side-effect of antagonizing IGF-1 or VEGF in phase II is catastrophic loss of endothelial cells (EC) resulting in exacerbation of phase I. The degree of hypoxia (phase I) determines phase II (NV).
SPECIFIC AIM I is to develop a mouse model of ROP reflective of the dual risk factors, O2 and low IGF-1. Our current model of ROP is based on O2-induced vessel loss alone. Two lines of CreLox conditional IGF-1 null mice with low total or low plasma IGF-1 will be subjected to varying O2 to determine: 1) the contributions of IGF-1 and O2 to both phases of ROP; 2) the paracrine and autocrine contribution of IGF-1; 3) the interaction between neural loss and vascular loss in ROP; 4) if IGF-1 replacement will support survival sufficiently in phase I to prevent the development of ROP.
SPECIFIC AIM II is to test strategies to suppress EC proliferation without impairing survival. Because VEGF and IGF-1 promote both proliferation and survival, we will determine if manipulation of other factors (Ang,2, iNOS and IGFBP-3) associated with NV inhibits NV without compromising vessel survival. A second strategy is to promote survival without promoting proliferation. We will determine if PIGF, a VEGFR1 agonist, can inhibit vaso-obliteration, without causing NV, which is dependent on VEGFR2. A third strategy is to target the EC proliferation signaling pathway (MAPK) to selectively inhibit proliferation. We will define in EC and in the new mouse model the selectivity of MEK1 inhibition for blocking vessel proliferation over survival. Parallel in vitro studies will be conducted to determine the relative contribution of Angl,2, iNOS and IGFBP-3 to EC proliferation and survival. We expect this work will form the foundation of a clinical trial for IGF-1 replacement to prevent ROP and help define new therapeutic strategies to inhibit NV without compromising vessel survival.
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