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: 10544744
• 负责人: Richard A. Lang
• 金额: $ 43.23万
• 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/10544744
• 关键词: Basic Science; Biological Models; Biology; Birth; Blood Vessels; Cell Survival; Cues; DRD2 gene; Data; Development; Dopamine; Dopamine Receptor; Educational process of instructing; Electrophysiology (science); Event; Eye; Eye diseases; Genetic; 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; Work; 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.

光通过河马通路调节眼部血管发育 我们最近的研究表明，视蛋白介导的光反应与发育计时有关 眼睛内血管发育的线索。480 nm蓝光对黑素蛋白(OPN4)的刺激 调节发育的视网膜神经元的数量，并通过氧气需求调节视网膜神经元的水平 VEGFA表达。我们还发现，出生后，神经蛋白酶(OPN5)在380 nm的紫光下 反应性视蛋白通常会抑制多巴胺的水平，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。 这个应用程序有两个目标。(1)在短期内，我们的目标是利用 以小鼠为模型系统，整合OPN4和OPN5途径的机制 玻璃体血管退行性变调节中的反应。我们的初步数据显示，河马 途径是正常的玻璃体退行性变所必需的，而且，它整合了OPN4和 OPN5光反应。这是一个重要的发现，因为已知河马通路在 在细胞生存中起着核心作用。为了理解这些机制，我们提出了三个实验。 AIMS将研究OPN4-VEGFA通路如何调节透明河马 反应，(目标2)OPN5-多巴胺途径如何调节玻璃体河马反应，以及 (目的3)两条光反应通路之间的串扰机制。在《目标3》中，我们将 还要确定光操作是否可以单独用于调节玻璃体血管 回归。这一点很重要，因为它与制定一项非 侵入性光刺激疗法治疗早产儿视网膜病变。当这项工作完成后， 我们希望对血管发育的机制有新的认识。 将为视网膜病变的新治疗选择奠定基础的眼睛 早产儿。