Light regulated vascular development of the eye

描述（由申请人提供）：光是一种无处不在的生物刺激。我们星球上的大多数光来自太阳，这密切反映在已经进化的光反应机制中。无论是单细胞绿色植物的向光性，植物的昼夜节律，还是人类的高敏锐度视觉，光都能激发各种各样的生物反应，这些反应具有根本的重要性。在这个应用程序中，我们提供的证据表明，在小鼠（因此，可能在人类）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，视网膜血管的生长是混杂的。在缺乏黑视素的光饲养小鼠中观察到相同的异常生长。我们有强有力的初步证据表明，眼血管发育不良与（1）神经营养因子BDNF的视网膜水平变化，（2）神经元数量增加，（3）通过需氧量改变VEGF表达水平有关。此外，令人惊讶的是，黑暗饲养的最大效果是在黑暗中饲养的幼崽从E16。我们的中心假设是：眼的发育受胎儿光-黑视素-BDNF通路调节，该通路调节神经元数量、VEGF表达，并最终调节出生后的血管形成。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是否是调节眼睛血管发育的必要和充分条件，（2）确定BDNF信号传导如何与光依赖性血管发育整合，（3）确定光反应通路中需氧量的作用。

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.