Mechanisms of intrinsic light responses in the ocular lens

我们通常认为神经视网膜是哺乳动物唯一的光反应组织。最近， 然而，已经表明非典型视蛋白视蛋白3（OPN 3，脑视蛋白）和视蛋白 5（OPN 5，neuropsin）在其他组织中表达。为了进一步调查，朗实验室 表明OPN 5介导皮肤和大脑中的光接收，OPN 3在脂肪中也是如此 组织.在所有情况下，这些视蛋白介导非视网膜细胞的直接、急性光反应。 组织.在这里，我们确定眼透镜作为一个内在的光敏感组织。透镜 在培养物中分离的一种细胞对蓝光（470 nm）显示出急性反应， 特性.根据初步的数据，OPN 3是需要的固有光响应的 透镜，我们进一步表明，光刺激的透镜抑制磷酸化的 水通道蛋白0，蛋白激酶A的底物。由于水通道蛋白0调节透镜 透明，我们假设OPN 3依赖的，内在的光反应调节 通过cAMP-PKA途径调节水通道蛋白活性，从而调节透镜的光学性能。 这一假设意味着透镜具有适应白天的不同光学状态， 夜间视力为了更深入地了解这种独特的透镜生物学，我们提出了三个 目的，（目的1），确定OPN 3在透镜中使用哪种G蛋白进行信号传导，（目的2）， 确认OPN 3信号传导机制，以及该信号传导对水通道蛋白的影响， 透镜透明度，包括白内障形成，以及（目的3），评估透镜OPN 3的影响 对透镜屈光力和眼睛屈光发育的影响。这个应用程序建立在一个长期的历史 Lang实验室对眼透镜感兴趣，并结合了Lang实验室在透镜细胞生物学方面的专业知识， Steve Bassnett和Rafael Grytz和Machelle Pardue的眼睛屈光发展。 鉴定眼透镜中的直接的、光依赖的和视蛋白依赖的光学变化是 因此，当这项工作完成时，它将从根本上改变我们的思维方式。 眼睛作为一个感光器官。还有一种可能性是，这项工作将确定 将透镜作为近视治疗的新靶点。

We normally think of the neural retina as the only light-responsive tissue of mammals. Recently, however, it has been shown that the atypical opsins Opsin 3 (OPN3, encephalopsin) and Opsin 5 (OPN5, neuropsin) are expressed in other tissues. Investigating this further, the Lang lab has shown that OPN5 mediates light reception in skin and brain and that OPN3 does so in adipose tissue. In all cases, these opsins mediate direct, acute light responsiveness of the non-retinal tissue. Here we identify the ocular lens as an intrinsically light sensitive tissue. Lenses isolated in culture show an acute response to blue (470 nm) light that changes their optical properties. According to preliminary data, OPN3 is required for the intrinsic light response of the lens and we further show that light stimulation of the lens suppresses the phosphorylation of the water channel Aquaporin 0, a substrate of protein kinase A. Since Aquaporin 0 regulates lens transparency, we hypothesize that an OPN3-dependent, intrinsic light response regulates aquaporin activity via the cAMP-PKA pathway and thus the optical performance of the lens. This hypothesis implies that the lens has distinct optical states adapted to daytime and nighttime vision. Seeking a deeper understanding of this unique lens biology, we propose three aims, (Aim 1), To determine which G-protein OPN3 uses for signaling in the lens, (Aim 2), To confirm the OPN3 signaling mechanism, and the influence of that signaling on aquaporins and lens transparency including cataractogenesis, and (Aim 3), To assess the influence of lens OPN3 on lens refractive power and eye refractive development. This application builds on a long history of interest in the ocular lens from the Lang lab and combines expertise in lens cell biology from Steve Bassnett and eye refractive development from Rafael Grytz and Machelle Pardue. Identification of a direct, light- and opsin-dependent optical change in the ocular lens is unexpected and so when complete, this work will fundamentally change the way we think of the eye as a light sensing organ. There is also the possibility that this work will identify the lens as a new target for myopia treatment.