Light regulated vascular development in the eye via the Hippo pathway

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Light regulated vascular development in the eye via the Hippo pathway Our recent studies show that opsin-mediated light responses function as developmental timing cues for vascular development within the eye. 480 nm blue light stimulation of melanopsin (OPN4) regulates the numbers of retinal neurons that develop and, via oxygen demand, the level of VEGFA expression. We have also shown that after birth, neuropsin (OPN5), a 380 nm violet light responsive opsin, normally suppresses the level of dopamine, a neuromodulator that has an anti- vascular activity through suppression of VEGFA signaling. This application has two goals. (1) In the near-term, we aim to understand, using the mouse as a model system, the mechanisms that integrate the OPN4 and OPN5 pathway responses in the regulation of hyaloid vessel regression. Our preliminary data show that the Hippo pathway is required for normal hyaloid regression and further, that it integrates the OPN4 and OPN5 light responses. This is an important finding because the Hippo pathway is known to play a central role in cell survival. To understand these mechanisms, we propose three experimental aims that will examine, (Aim 1) how the OPN4-VEGFA pathway regulates hyaloid Hippo responses, (Aim 2) how the OPN5-dopamine pathway regulates hyaloid Hippo responses, and (Aim 3) the mechanisms of cross-talk between the two light response pathways. In Aim 3, we will also determine whether light manipulations alone can be used to regulate hyaloid vessel regression. This is important because it is dovetails with long-term goal (2) of devising a non- invasive, light stimulation therapy for retinopathy of prematurity. When this work is complete, we expect to emerge with new knowledge of the mechanisms of vascular development in the eye that will lay the groundwork for a new therapeutic option for retinopathy of prematurity.