Regulation of the intrinsic melanopsin-based light response in ipRGCs

建议书摘要/摘要： 在哺乳动物的视网膜中，有一小部分视网膜神经节细胞(RGC)发挥着自主功能 光感受器和光反应不依赖于视杆/视锥驱动的突触输入。这些本质上 光敏性视网膜节细胞(又称ipRGCs)将光信息传递给大脑，以调节几个依赖于光的 这些过程包括昼夜节律光携带、瞳孔光反射(PLR)、睡眠和情绪。IpRGC使用 光色素黑素和G蛋白偶联的光转导级联反应光，并且是 现在已知由5个不同的亚型(M1-5)组成，可以根据形态和 电生理标准、投射靶点和转录因子表达。目前，存在一个 我们对黑素及其下游光转导的调节方式的理解存在重大差距 不同的ipRGC亚型中的通路控制着不同的光介导行为。根据我们的初步数据， 这项拟议研究的目标是在目标I中确定黑素蛋白翻译后修饰的作用 在ipRGC介导的体内行为中，以及在AIM II中，允许不同的ipRGC的光传导成分 子类型以内在地检测光线并影响ipRGC-子类型的特定行为。这些研究将提供 对光影响范围广泛的生化和分子机制的批判性理解 通过调节昼夜节律、睡眠、情绪和学习对人类健康和表现的影响 &记忆。

Proposal Summary/Abstract: In the mammalian retina, there is a small subset of retinal ganglion cells (RGCs) that function as autonomous photoreceptors and exhibit light responses independent of rod/cone-driven synaptic input. These intrinsically photosensitive RGCs (known as, ipRGCs) relay light information to the brain to regulate several light-dependent processes, such as circadian photoentrainment, the pupillary light reflex (PLR), sleep, and mood. ipRGCs use the photopigment melanopsin and a G-protein coupled phototransduction cascade to respond to light, and are now known to comprise 5 different subtypes (M1-5) that can be differentiated based on morphological and electrophysiological criteria, projection targets, and transcription factor expression. Currently, there exists a major gap in our understanding of how the regulation of melanopsin and its downstream phototransduction pathways in different ipRGC subtypes govern distinct light-mediated behaviors. Based on our preliminary data, the goal of the proposed research is to determine, in Aim I, the role of melanopsin posttranslational modifications in ipRGC-mediated behaviors in vivo, and in Aim II, the phototransduction components that allow distinct ipRGC subtypes to intrinsically detect light and influence ipRGC-subtype specific behaviors. These studies will provide a critical understanding of the biochemical and molecular mechanisms by which light influences a wide range effects on human health and performance through the regulation of circadian rhythms, sleep, mood, and learning & memory.