The PI hypothesis is that the cells of the aqueous outflow pathway can modulate aqueous humor outflow resistance through changes in cell shape, contraction and attachment; that the cytoskeleton in outflow pathway cells (both the inner wall of Schlemm's canal (SC) and the juxtacanalicular (JCT) cells) is involved in these cellular events; that in response to increases in intraocular pressure (IOP) the outflow pathway tissue distends and stretches both the cells in the JCT and inner wall of SC; that the resulting changes in cellular tension produce reorganization of cytoskeletal proteins that may be different in the two cell types, that then through induced changes in cell shape and attachment alter the dimension or direction of the flow pathway through the JCT and inner wall of SC, which allows a compensatory increase in fluid outflow. The PI hypothesizes that overexpression of constitutively active rho and/or alteration of myosin light chain phosphorylation will mimic the cytoskeletal (and cell shape and attachment) effects that occur with increased flow and/or stretching, and that their underexpression will interfere with these responses as well as that to certain (but not all) cytoskeletal drugs such as ethacrynic acid (ECA), ticrynafen and vinblastine.
The Specific Aims i nclude: 1)To characterize the resulting cytoskeletal protein as well as cell shape and attachment changes in both normal trabecular meshwork (TM) and SC cells, and in cells where various key cytoskeletal proteins such as rho, myosin light chain kinase and phosphatase, and focal adhesion kinase (FAK) have been either constitutively overexpressed, underexpressed, or rendered inactive by dominant negative mutant technology in both flow/no flow and stretching experiments. 2)To reevaluate the cell shape, attachment, contraction, and cytoskeletal protein staining effects of ECA, indacrinone, ticrynafen, vinblastine, cytochalasin B, H-7 and BDM in both TM and now SC cells that similarly over- or underexpress these key cytoskeletal proteins, as in 1. 3)For both 1 and 2 to correlate these findings with quantitative aqueous humor outflow and morphological studies of excised porcine and especially, organ cultured human eyes (anterior segments). The PI believes that these studies will potentially provide important new insight into both the modulation of normal outflow pathway cell function, and abnormal function that might be present in certain glaucomas.
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