TRPV4 as a remote controller of lens function

University Of Arizona, Tucson AZ

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Abstract

To function normally, all cells must maintain ion homeostasis and regulate water content. These actions require active Na-K transport provided by Na,K-ATPase. The lens, however, is a syncytium-like structure made up almost entirely of fiber cells that have little or no Na,K-ATPase activity. Lens ion and water homeostasis relies on Na,K-ATPase activity in a small number of cells at the periphery of epithelium monolayer. Therefore, the function of the epithelium must be integrated with the needs of the fiber mass. We envision there to be a remote control mechanism that adjusts Na,K-ATPase activity to match increases or decreases of ion leakage that may occur a considerable distance away. The mechanism depends on TRPV4, an ion channel. We propose studies to determine the detailed workings of this remote control mechanism and its functional impact on the lens. Aim 1 includes studies to determine how the lens uses TRPV4 to sense a change in the fiber mass and activate Src Family Tyrosine Kinases (SFKs) in the epithelium. Studies proposed in Aim 2 will determine how lens epithelial cells use SFKs to change Na,K-ATPase activity. Aim 3 describes the use of magnetic resonance imaging (MRI) and atomic absorption spectroscopy to measure the impact of the TRPV4 remote control mechanism on lens water and ion homeostasis. The significance to human well-being is that cataract is frequently associated with failed homeostasis.