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A. Whitlock, T. Mixon, B. McKnight, D. S. Rice; LIMK2 Modulates IOP in Mice. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2147.
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Cytoskeletal modulating agents are potential therapies for ocular hypertension and glaucoma. The most widely studied target has been Rho-associated coiled coil containing protein kinase (ROCK). ROCK phosphorylates a number of effector molecules that could be important in regulating IOP. The purpose of this study was to identify genes downstream of ROCK that are responsible for mediating IOP regulation in mice.
Intraocular pressure was measured in mice deficient in either myosin light chain kinase (MLCK), LIM domain kinase 1 (LIMK1), or LIM domain kinase 2 (LIMK2). IOP was also measured in mice deficient in both LIMK1 and LIMK2 that were generated through interbreeding LIMK1 and LIMK2 knockouts. ROCK inhibitors were applied topically in mice deficient in either LIMK1 or LIMK2 and the IOP response was measured.
Mice deficient in MLCK and LIMK1 exhibited no discernible IOP phenotype. In contrast, knockout of LIMK2 resulted in a significant decrease in IOP compared to wild type littermates. Mice deficient in both LIMK1 and LIMK2 exhibited a significant decrease in IOP. Knockout of LIMK2, but not LIMK1, abrogated the IOP lowering effect of ROCK inhibitors.
Genetic and pharmacological evidence establishes LIMK2 as a necessary downstream target of ROCK-induced IOP regulation in mice. These results identify LIMK2 as a new target for lowering IOP.
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