Melatonin Signaling in Photoreceptors

褪黑素在体内许多生理功能的调节中起着重要的作用 在视网膜内。多项研究表明，视网膜中的褪黑素合成主要发生在 在夜间，它的水平在白天很低。褪黑素通过与G结合发挥作用 蛋白质偶联受体称为褪黑素受体1型(MT1)和2型(MT2)。MT1和MT2 受体激活了各种各样的信号通路，两种受体都存在于 脊椎动物的光感受器，在那里它们可能形成MT1/MT2异构体(MT1/2小时)。之前的研究已经 也证明了褪黑素可能在保护光感受器免受 氧化应激，并能保护感光细胞免受细胞凋亡。关键的是，褪黑素信号是 在衰老过程中参与光感受器功能和生存能力的调节。最后，新的 实验证据表明，高脂饮食(HFD)可显著降低 MT1信号缺失小鼠暗适应ERG a波和b波的波幅。这样做的目的是 应用是阐明褪黑素信号在光感受器调节中的作用 并确定褪黑素是否可以作为对抗视网膜的有用工具 精神错乱。本申请包括两个具体目的。在具体目标1中，我们将产生一个 在褪黑素熟练的遗传背景下，杆状特异性MT1基因敲除小鼠。在具体目标2中，我们 将探讨MT1/2小时信号转导保护光感受器细胞HFD的机制(S)。在我们的 研究，我们将使用广泛的新的和技术先进的技术以及我们将 开发新的转基因小鼠品系。我们的建议将为我们提供关于 褪黑素信号在光感受器健康中的调制作用。

Melatonin is an important player in the regulation of many physiological functions within the body and within the retina. Several studies have shown that melatonin synthesis in the retina primarily occurs during the night and its levels are low during the day. Melatonin exerts its influence by binding to G protein-coupled receptors named melatonin receptor type 1 (MT1) and type 2 (MT2). MT1 and MT2 receptors activate a wide variety of signaling pathways and both receptors are present in the vertebrate photoreceptors where they may form MT1/MT2 heteromers (MT1/2h). Previous studies have also demonstrated that melatonin may play an important role in protecting photoreceptors from oxidative stress and can protect photoreceptors from apoptosis. Critically, melatonin signaling is involved in the modulation of photoreceptor functioning and viability during aging. Finally, new experimental evidence indicates that high fat diet (HFD) leads to a significant decrease in the amplitude of a- and b-wave of the scotopic ERGs in mice lacking MT1 signaling. The goal of this application is to elucidate the role of melatonin signaling plays in in the modulation of photoreceptor functioning and to determine if melatonin may represent a useful tool in the fight against retinal disorders. The present application comprises two specific aims. In specific aim 1 we will produce a rod specific MT1 knock out mice in a melatonin proficient genetic background. In specific aim 2 we will investigate the mechanism(s) by which MT1/2h signaling protects photoreceptor cells HFD. In our research, we will use a wide array of new and technologically advanced techniques as well as we will develop new lines of transgenic mice. Our proposal will provide important insights about the role of melatonin signaling in the modulation of photoreceptor health.