PROJECT SUMMARY Retinopathy of prematurity (ROP) is among the most common morbidities affecting premature or low birth weight infants and is a major cause of long-term visual and non-vision related morbidity. ROP is a disease of low birth weight survivors, but is often preceded temporally by inflammatory conditions in both the prenatal and postnatal period. Limiting exposure to excess oxygen and the recent advent of anti- angiogenic compounds are the foundation of ROP treatment, but these approaches are compounded by increased mortality and poorer cognitive outcomes in low birth weight infants who are maintained at lower supplemental oxygen or received bevacizumab (anti-VEGF) for ROP. These findings indicate a poor understanding of disease pathogenesis and contribution of co-morbid diseases and inflammation to ROP development. Clinical observations of persons at risk for retinal neovascularization and inflammation, as seen in neurofibromatosis type 1 (NF1), suggest that inflammatory monocytes and macrophages play a vital role in aberrant retinal angiogenesis and ROP. Neurofibromin, the protein encoded by the gene causing NF1, functions as a master regulator of macrophage polarization, and inactivating mutations in the Nf1 gene result in mobilization of pro-inflammatory monocytes and macrophages in mice and humans. Neurofibromin-deficient macrophages take on a distinct molecular and metabolic phenotype, characterized by enhanced production of reactive oxygen and nitrogen species and over-dependence on glycolysis via upregulation of phosphofructokinase-1 (PFK-1) activity. Further, neurofibromin-deficient macrophages are pro-angiogenic, but also support pathologic retinal neovascularization. In Aim 1, we will interrogate neurofibromin-regulated pathways that induce inflammatory macrophage polarization to identify how they promote endothelial cell proliferation, migration, and capillary formation. Aim 2 will examine glucose uptake and utilization in neurofibromin- deficient macrophages using in vitro and in vivo techniques with specific focus on macrophage metabolism as a therapeutic target for the treatment/prevention of retinal neovascularization. Finally, in Aim 3, we will capitalize on pilot data demonstrating a mobilization of inflammatory monocyte subsets in neonates with severe ROP. Here, we will longitudinally examine circulating inflammatory monocytes in neonates ?at risk? for severe ROP to identify discrete monocyte subsets as a biomarker for ROP and define the contribution of neurofibromin-regulated signaling to inflammatory monocyte mobilization in neonates with ROP. At their conclusion, the proposed studies will define the contribution of inflammatory macrophages to pathologic retinal neovascularization and identify a biomarker for severe ROP requiring treatment.
- National Eye Institute: $433,758.00