Light regulated vascular development of the eye

描述（申请人提供）：光是一种无所不在的生物刺激。我们星球上的大多数光来自太阳，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，还是人类的高灵敏度视觉，光都会引发各种各样的生物反应，这些反应都是至关重要的。在这个应用中，我们提供的证据表明，在老鼠（因此，可能在人类）光是一个重要的刺激眼睛发育。出乎意料的是，我们发现黑暗饲养的新生小鼠血管发育异常，其中玻璃体血管退化迟缓，视网膜血管混杂生长。在缺乏光色素黑视素的小鼠中也观察到同样的异常生长。我们有强有力的初步证据表明，眼部血管发育不良与(1)视网膜神经营养因子BDNF水平的变化，(2)神经元数量的增加，以及(3)通过氧气需求改变VEGF表达水平有关。此外，令人惊讶的是，黑暗饲养的最大影响是在E16开始在黑暗中饲养的幼崽身上发现的。我们的中心假设是：眼部发育是由胎儿光-黑视素- bdnf通路调节的，该通路调节神经元数量、VEGF表达，并最终调节出生后的血管模式。我们提出了三个实验目的：(1)确定胎儿黑视素途径的光激活是否对调节眼睛血管发育是必要和充分的；(2)确定BDNF信号如何与光依赖性血管发育整合；(3)确定氧气需求在光反应途径中的作用。

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.