TRP Channels as Master Controllers of Lens Function

为了正常运作，所有细胞都必须保持离子平衡并调节水分含量。 这种透镜是不寻常的，因为它是由一大堆纤维细胞组成的，这些纤维细胞 不能独立维持离子和水的动态平衡。纤维细胞依赖于 晶状体表面单层上皮细胞离子传输机制的研究。那，K- ATPase和NKCC1活性尤为重要。监视和控制这一点 安排，镜头已经变得依赖于精致的专业遥控器 利用TRPV4和TRPV1通道的机制。一个TRPV4反馈环路 纤维肿胀，增加Na，K-ATPase活性进行补偿。A-TRPV1 反馈环感知纤维质量的收缩，并增加NKCC1活性以 补偿。反馈循环很重要。他们解释了动态平衡的调节 晶状体离子传输以及细胞内静水压力，它们符合 马蒂亚斯的晶状体循环模型。TRPV4和TRPV1似乎是 晶状体动态平衡。具体目标是：(1)检验假设 TRPV4/半通道/Na，K-ATPase对肿胀牵张的反应涉及一个功能环节 在TRPV4和肌动蛋白细胞骨架之间；(2)检验假设 TRPV1/ERK/NKCC1对收缩的反应涉及TRPV1之间的功能联系 和微管蛋白细胞骨架；(3)探讨晶状体离子和水的保存机制。 动态平衡。目标1和目标2侧重于尚未回答的机械问题 TRPV4和TRPV1通过相反的机械刺激激活，依赖于TRPV4 半通道开放，以及NKCC1激活机制。目标3跟进试点 支持较慢的动态平衡反应的储备机制或作为 故障保护备份。拟议中的研究对人类视力具有重要意义。 因为透镜透明度和折射率梯度的保持依赖于离子 和水的动态平衡。

To function normally, all cells must maintain ion homeostasis and regulate water content. The lens is unusual because it is made from a packed mass of fiber cells that are incapable of independently maintaining ion and water homeostasis. The fiber cells rely on ion transport mechanisms in a monolayer of epithelial cells at the lens surface. Na,K- ATPase and NKCC1 activity are particularly important. To monitor and control this arrangement, the lens has come to rely on exquisitely specialized remote control mechanisms that utilize TRPV4 and TRPV1 channels. A TRPV4 feedback loop senses swelling in the fiber mass and increases Na,K-ATPase activity to compensate. A TRPV1 feedback loop senses shrinkage in the fiber mass and increases NKCC1 activity to compensate. The feedback loops are important. They explain homeostatic regulation of lens ion transport as well as intracellular hydrostatic pressure, and they fit with the Mathias model of lens circulation. TRPV4 and TRPV1 appear to be master controllers of lens homeostasis. The specific aims are: (1) Test the hypothesis that the TRPV4/hemichannel/Na,K-ATPase response to swelling stretch involves a functional link between TRPV4 and the actin cytoskeleton; (2) Test the hypothesis that the TRPV1/ERK/NKCC1 response to shrinkage involves a functional link between TRPV1 and the tubulin cytoskeleton; (3) Explore reserve mechanisms of lens ion and water homeostasis. Aims 1 and 2 focus on unanswered mechanistic questions regarding TRPV4 and TRPV1 activation by opposing mechanical stimuli, TRPV4-dependent hemichannel opening, and the mechanism of NKCC1 activation. Aim 3 follows up pilot studies on reserve mechanisms that support slower homeostatic responses or serve as a fail-safe backup. The proposed studies are highly significant as regards human vision because preservation of lens transparency and refractive index gradient depends on ion and water homeostasis.