TRP Channels as Master Controllers of Lens Function

为了正常发挥功能，所有细胞都必须维持离子稳态并调节水含量。 这种透镜很不寻常，因为它是由大量的纤维细胞组成的， 不能独立维持离子和水的体内平衡。纤维细胞依靠 在透镜表面的单层上皮细胞中的离子转运机制。Na，K- ATP酶和NKCC 1活性尤其重要。来监控和控制这一切 在这种安排下，透镜依赖于精致的专业遥控器 利用TRPV 4和TRPV 1通道。TRPV 4反馈回路感测 在纤维团中膨胀并增加Na，K-ATP酶活性以补偿。的trpv 1 反馈环感觉到纤维团的收缩，并增加NKCC 1活性， 补偿。反馈回路很重要。他们解释了 透镜离子转运以及细胞内流体静压，它们与 透镜循环的Mathias模型。TRPV 4和TRPV 1似乎是 透镜体内平衡。具体目的是：（1）检验假设， TRPV 4/hemicannel/Na，K-ATP酶对肿胀牵张的反应涉及功能性连接 TRPV 4与肌动蛋白细胞骨架之间的关系;（2）检验TRPV 4与肌动蛋白细胞骨架之间的关系的假设。 TRPV 1/ERK/NKCC 1对收缩的反应涉及TRPV 1/ERK/NKCC 1之间的功能联系 （3）探讨透镜离子和水的储备机制 体内平衡目标1和2侧重于未回答的机械问题， TRPV 4和TRPV 1通过相反的机械刺激激活，TRPV 4依赖性 半通道开放和NKCC 1激活的机制。目标3跟踪飞行员 研究储备机制，支持较慢的稳态反应或作为一个 自动防故障备份这些研究对人类视觉具有重要意义 因为透镜透明度和折射率梯度的保持取决于离子 和水平衡

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.