Regulation of eye development by an Opsin5-dopamine pathway

Opsin5-多巴胺通路调节眼睛发育

• 批准号: 9263420
• 负责人: P Michael Iuvone
• 金额: $ 48.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9263420
• 关键词: Acute; Address; Adult; Amacrine Cells; Behavior; Biology; Birds; Birth; Blood Vessels; Breeding; Cell physiology; Cells; Circadian Rhythms; Clinical; Collaborations; Data; Detection; Development; Dopamine; Dopamine Receptor; Encapsulated; Eye; Eye Development; Future; Genes; Genetic; Hypotension; Light; Lighting; Mammals; Methods; Mutant Strains Mice; Neuromodulator; Ocular Physiology; Opsin; Optics; Participant; Pathway interactions; Photosensitivity; Physiological; Premature Infant; Production; Proteins; Regulation; Retina; Retinal; Retinal Ganglion Cells; Retinopathy of Prematurity; Role; Sensory; Signal Transduction; Source; Stimulus; Structure; Suggestion; Tissues; Tyrosine 3-Monooxygenase; VEGFA gene; Vascular Diseases; Vascular Endothelial Cell; Vision; Visual system structure; Work; circadian pacemaker; clinically relevant; design; gain of function; high risk; insight; loss of function; melanopsin; receptor; response; retinal angiogenesis; tool; uptake; vessel regression

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.

摘要 -- 视蛋白5-多巴胺通路对眼睛发育的调控。神经蛋白酶(OPN5)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ip5RGC)中表达。 众所周知，OPN5对近紫外线波长做出反应，并对视网膜生物钟进行光包裹。超越 关于神经蛋白酶在任何组织中的生理功能，人们对此知之甚少。 在这个应用中，我们揭示了在眼睛的发育过程中，OPN5反应通路 调节关键神经调节剂多巴胺(DA)的水平。众所周知，DA在 但在视觉系统中，最具特点的是其调节适应性反应的作用 夜间和日间照明。我们还发现DA对血管有直接的影响。 眼睛里的发育。初步数据表明，DA是血管的负性调节因子 促进玻璃体血管退缩和抑制视网膜血管生成的反应。因此，DA充当一个 与VEGFA相反，VEGFA是一种有利于血管的刺激。我们的初步发现提出了中心假说： OPN5-多巴胺途径调控眼部血管发育。我们的假设包含了 双重提示OPN5调节DA活性和DA直接调节血管发育 眼睛。我们提出了三个实验目标，旨在解决神经蛋白酶活性之间的关系 和DA的产生：目标1：确定ip5RGC是否与多巴胺能形成物理联系 无长突细胞。目的2：评估OPN5是通过视网膜昼夜节律还是通过视网膜昼夜节律来调节多巴胺 钟。目的3：探讨多巴胺调节眼部血管发育的机制。什么时候 完成后，这些分析将提供重要的新见解，神经蛋白酶在生理学中的作用。 视觉系统。这一分析在临床上也是相关的，因为DA-血管通路可能是 早产儿DA治疗(用于低血压)与 严重早产儿视网膜病变的潜在致盲血管过度生长。