Regulation of eye development by an Opsin5-dopamine pathway

摘要 通过视蛋白5-多巴胺途径调节眼睛发育。Neuropsin（OPN 5）是一种非典型的 我们显示的视蛋白在脊椎动物视网膜的视网膜神经节细胞（我们称之为ip 5 RGCs）中表达。 已知OPN 5对近紫外波长有反应，并对光诱导视网膜生物钟。超出 关于神经视蛋白在任何组织中的生理功能，人们知之甚少。 在本申请中，我们揭示了在眼睛发育过程中， 调节关键的神经调节剂多巴胺（DA）的水平。已知DA在 视觉系统，但其中，最好的特点是它的作用，调节适应性反应， 夜间和日间照明。我们还揭示了DA直接影响血管生成的重要作用， 眼内的发展。初步数据表明，DA作为血管的负调节剂， 促进玻璃体血管消退和抑制视网膜血管生成的反应。因此，DA充当 与VEGFA相反，VEGFA是一种促进血管的刺激物。我们的初步研究结果表明了中心假设： OPN 5-多巴胺通路调节眼睛的血管发育。我们的假设包含了 这两点都表明，OPN 5调节DA活性，DA直接调节血管发育， 眼睛我们提出了三个实验目的，旨在解决neuropsin活性之间的关系， 目的1：确定ip 5 RGCs是否与多巴胺能神经元形成物理连接， 无长突细胞目的2：评估OPN 5是否急性或通过视网膜昼夜节律调节多巴胺 时钟目的3：探讨DA调节眼血管发育的机制。当 完成后，这些分析将提供重要的新的见解neuropsin的生理作用， 视觉系统该分析也具有临床相关性，因为DA-血管通路可能是 早产儿DA治疗（低血压）与 严重早产儿视网膜病变的潜在致盲性血管过度生长。

ABSTRACT   Regulation of eye development by an Opsin 5-dopamine pathway. Neuropsin (OPN5) is an atypical opsin that we show is expressed in retinal ganglion cells of the vertebrate retina (we call these ip5RGCs). OPN5 is known to respond to near-UV wavelengths and to photoentrain a retinal circadian clock. Beyond this, very little is known about the physiological function of neuropsin in any tissue. In this application we reveal that during development of the eye, an OPN5 response pathway regulates levels of the crucial neuromodulator dopamine (DA). DA is known to have several functions in the visual system but among them, the best characterized is its role in regulating the adaptive response to nighttime and daytime lighting. We also reveal that DA has an important role directly influencing vascular development within the eye. Preliminary data suggest that DA acts as a negative regulator of vascular responses to promote hyaloid vessel regression and suppress retinal angiogenesis. Thus, DA acts as a counter to VEGFA, a pro-vascular stimulus. Our preliminary findings suggest the central hypothesis: An OPN5-dopamine pathway regulates vascular development of the eye. Our hypothesis incorporates the dual suggestions that OPN5 regulates DA activity and that DA directly regulates vascular development in the eye. We propose three experimental Aims designed to address the relationship between neuropsin activity and DA production: Aim 1: To determine whether ip5RGCs form physical connections with dopaminergic amacrine cells. Aim 2: To assess whether OPN5 regulates dopamine acutely or via the retinal circadian clock. Aim 3: To determine the mechanism by which DA regulates vascular development in the eye. When complete, these analyses will provide important new insights on the role of neuropsin in the physiology of the visual system. This analysis is also clinically relevant because a DA-vascular pathway is probably the explanation for the association between DA treatment of premature infants (for hypotension) and the potentially blinding vascular overgrowth of severe retinopathy of prematurity.