Light regulated vascular development of the eye

描述(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来自太阳，这在进化的光反应机制中得到了密切的反映。无论是单细胞绿藻的趋光性，还是植物的昼夜节律性，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，这是至关重要的。在这一应用中，我们提供了证据，证明在老鼠(因此，很可能在人类)中，光是眼睛发育的重要刺激因素。出乎意料的是，我们发现黑暗饲养的新生小鼠表现出血管发育异常，其中玻璃体血管退化缓慢，视网膜血管生长紊乱。在缺乏光色素黑素的光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(1)神经营养因子BDNF的视网膜水平改变，(2)神经元数量增加，以及(3)通过氧需求改变VEGF的表达水平有关。此外，令人惊讶的是，黑暗饲养的效果最大的是从E16开始在黑暗中长大的幼崽。我们的中心假设是：眼睛发育受胎儿光-黑素蛋白-脑源性神经营养因子通路的调节，该通路调节神经元数量、血管内皮生长因子的表达，最终调节出生后的血管构型。我们提出了三个实验目标：(1)确定光激活胎儿黑素途径是否对调节眼部血管发育是必要和充分的，(2)确定BDNF信号如何与光依赖的血管发育相结合，以及(3)确定氧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.