PROJECT SUMMARY Retinopathy of prematurity (ROP) is a potentially blinding vaso-proliferative disease frequently seen in prematurely born infants with lifelong consequences for both the infant and society. The c-type lectin, Surfactant Protein A (SP-A), is an immunomodulatory protein, found to be deficient in prematurely born infants. Lack of SP-A is associated with lung disease of prematurity and a temporal association with pulmonary vascular growth factors has been previously reported. We previously discovered that SP-A is expressed in the Müller retina and plays an important role in neovascular disease (NV) with a pro-angiogenic phenotype. Our preliminary data now shows SP-A promotes early retinal vascular development, and conversely, lack of SP-A is seen in response to hyperoxia in rodent models. SP-A has a positive association with expression of retinal vascular endothelial growth factor (VEGF), cytoskeleton proteins and associated chaperones necessary for both cytoskeleton and VEGF folding. Our results suggest that deficiency of SP-A leads to reduced vascular growth in endothelial cells both in the rodent retina and in vitro impacting retinal angiogenesis. Conversely, in the second stage, SP-A acts in a proangiogenic fashion to drive NV. Given that current anti-VEGF therapies for ROP may result in delayed re-appearance of NV and may also depress systemic VEGF levels with consequences for the growing preterm infant, there is a critical need to develop safe and targeted therapies for ROP and most importantly- to prevent it. We hypothesize that the SP-A protein and associated pathways represent novel therapeutic targets to rescue early hyperoxia and prematurity related vascular arrest. It is imperative to understand the mechanisms for these complex cell-intrinsic properties. In this proposal we will examine cytoskeleton, chaperone and S-A receptor molecules using transgenic strains with targeted deletion of SP-A and Myo18A receptor in Müller and endothelial cells. We will examine the association between SP-A and the chaperone aCrystallinB which drive post-translational modification of cytoskeleton and vascular growth factors. The goals of this proposal are to characterize the SP-A/chaperone/VEGF axis, to confirm Myo18A as the SP-A receptor and study the impact of SP-A on endothelial cell cytoskeleton and endothelial cell function. Finally, we will test the therapeutic potential of targeting SP-A protein in early disease in a rodent ROP model. These goals have clear