Light regulated vascular development of the eye

光调节眼睛血管发育

• 批准号: 8731362
• 负责人: DAVID Richard COPENHAGEN
• 金额: $ 9.28万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731362
• 关键词: Adopted; Affect; Biological; Blood Vessels; Brain-Derived Neurotrophic Factor; Circadian Rhythms; Complex; Darkness; Data; Defect; Development; Educational process of instructing; Exhibits; Eye; Eye Development; Eye diseases; Fetus; Genetic; Goals; Green Algae; Growth; Heterozygote; Homozygote; Human; Hypoxia; Lead; Light; Mediating; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Neonatal; Neurons; Obstruction; Optics; Oxygen; Oxygen measurement, partial pressure, arterial; Pathway interactions; Pattern; Photophobia; Phototropism; Planets; Plants; Public Health; Publishing; Regulation; Retinal; Retinal Ganglion Cells; Retinopathy of Prematurity; Risk; Role; Signal Transduction; Stimulus; System; Testing; The Sun; Time; Vascular Endothelial Growth Factors; Vision; Work; dark rearing; fetal; melanopsin; neurotrophic factor; postnatal; public health relevance; pup; response; retina blood vessel structure

DESCRIPTION (provided by applicant): Light is an all-pervasive biological stimulus. Most light on our planet comes from the sun and this is closely reflected in the mechanisms of light response that have evolved. Whether it is the phototropism of a unicellular green alga, the circadian entrainment of plants or high-acuity vision in humans, light elicits a huge variety of biological responses that are of fundamental importance. In this application, we provide evidence that in the mouse (and thus, probably in the human) light is an important stimulus for eye development. Unexpectedly, we found that dark reared neonatal mice exhibit abnormal vascular development in which the regression of hyaloid vessels is retarded and the growth of retinal vessels is promiscuous. The same abnormal growth is observed in light reared mice lacking the photopigment melanopsin. We have strong preliminary evidence that the maldevelopment of the ocular vessels is associated with (1) changes in the retinal level of the neurotrophin BDNF, (2) increased neuron number, and (3) altered VEGF expression level via oxygen demand. Also, surprisingly, the maximal effect of dark rearing is found in pups raised in darkness from E16. Our Central Hypothesis is: Ocular development is regulated by a fetal light-melanopsin-BDNF pathway that regulates neuron number, VEGF expression, and ultimately, postnatal vascular patterning. We propose three experimental aims: (1) To establish whether light activation of the melanopsin pathway in the fetus is necessary and sufficient to regulate vascular development in the eye, (2) to determine how BDNF signaling integrates with light-dependent vascular development, and (3) to define the role of oxygen demand in the light response pathway.

描述（由申请人提供）：光是一种无处不在的生物刺激。我们星球上的大部分光都来自太阳，这在已经进化的光响应机制中得到了密切的反映。无论是单细胞绿藻的向光性、植物的昼夜节律还是人类的高敏锐度视觉，光都会引发各种各样的生物反应，这些反应至关重要。在此应用中，我们提供的证据表明，在小鼠（因此也可能在人类）中，光是眼睛发育的重要刺激。出乎意料的是，我们发现黑暗饲养的新生小鼠表现出异常的血管发育，其中玻璃体血管的退化被延迟并且视网膜血管的生长是混杂的。在缺乏感光色素黑视蛋白的光照饲养的小鼠中也观察到了同样的异常生长。我们有强有力的初步证据表明，眼血管发育不良与以下因素有关：(1) 视网膜神经营养蛋白 BDNF 水平的变化，(2) 神经元数量增加，以及 (3) 通过需氧量改变 VEGF 表达水平。此外，令人惊讶的是，从 E16 开始，黑暗饲养的效果最大的是在黑暗中饲养的幼崽。我们的中心假设是：眼睛发育受到胎儿光-黑视蛋白-BDNF 通路的调节，该通路调节神经元数量、VEGF 表达，并最终调节出生后血管模式。我们提出了三个实验目标：（1）确定胎儿黑视蛋白通路的光激活对于调节眼睛血管发育是否是必要和充分的，（2）确定BDNF信号如何与光依赖性血管发育整合，以及（3）定义需氧量在光响应通路中的作用。