Light regulated vascular development in the eye via the Hippo pathway

光通过河马途径调节眼睛血管发育

• 批准号: 10322455
• 负责人: Richard A. Lang
• 金额: $ 41.94万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322455
• 关键词: Basic Science; Biological Models; Biology; Birth; Blood Vessels; Cell Survival; Cells; Cues; DRD2 gene; Data; Development; Dopamine; Dopamine Receptor; Educational process of instructing; Event; Eye; Eye diseases; Goals; Health; Human; KDR gene; Knowledge; Light; Link; Mediating; Methods; Mus; Neonatal; Neuromodulator; Opsin; Oxygen; Pathway interactions; Play; Pregnancy; Production; Public Health; Publishing; Regulation; Retina; Retinopathy of Prematurity; Role; Signal Transduction; Stimulus; Testing; Text; Therapeutic; VEGFA gene; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Viola; Visual system structure; Work; base; blood vessel development; experimental study; fetal; interest; loss of function; melanopsin; novel therapeutics; overexpression; response; retinal neuron; vessel regression

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.

光通过Hippo途径调节眼内血管发育 我们最近的研究表明，视蛋白介导的光反应的功能，作为发展的时间 眼内血管发育的线索。480 nm蓝光刺激黑视蛋白（OPN 4） 调节发育的视网膜神经元的数量，并通过氧需求， VEGFA表达我们还表明，出生后，neuropsin（OPN 5），一种380 nm的紫光， 反应视蛋白，通常抑制多巴胺的水平，多巴胺是一种神经调节剂，具有抗 血管活性通过抑制VEGFA信号传导。 这个应用程序有两个目标。(1)在短期内，我们的目标是了解，使用 小鼠作为模型系统，整合OPN 4和OPN 5通路的机制 玻璃体血管退化的调节反应。我们的初步数据显示河马 通路是正常玻璃体消退所必需的，并且进一步地，它整合了OPN 4和 OPN 5光反应。这是一个重要的发现，因为河马途径是众所周知的， 在细胞存活中起着重要作用。为了理解这些机制，我们提出了三个实验 目的是研究（目的1）OPN 4-VEGFA通路如何调节透明海马 （目的2）OPN 5-多巴胺通路如何调节透明海马反应，以及 (Aim 3）两条光响应通路之间的串扰机制。在目标3中，我们 也确定是否光操作可以单独用于调节玻璃体血管 回归分析这一点很重要，因为它与设计一个非政府组织的长期目标（2）是不一致的。 早产儿视网膜病变的侵入性光刺激治疗。当这项工作完成后， 我们希望能对血管发育的机制有新的认识， 这只眼睛将为视网膜病变的新治疗选择奠定基础。 早产