title: The effect of biophysical attributes of the ocular trabecular meshwork associated with glaucoma on the cell response to therapeutic agents.
abstract: Glaucoma is a devastating neurodegenerative disease, which can lead to vision loss and is associated with irreversible damage to retinal ganglion cells. Although the mechanism of disease onset remains unknown, we have recently demonstrated that the stiffness of the ocular trabecular meshwork (HTM) increases dramatically in human donor eyes with a history of glaucoma. Here we report that polyacrylamide hydrogels, which mimic the compliant conditions of normal and glaucomatous HTM, profoundly modulate cytoskeletal dynamics and the elastic modulus of the overlying HTM cells. Substratum compliance also modulates HTM cell response to Latrunculin-B, a cytoskeletal disrupting agent currently in human clinical trials for the treatment of glaucoma. Additionally, we observed a compliance-dependent rebound effect of Latrunculin-B with an unexpected increase in HTM cell elastic modulus being observed upon withdrawal of the drug. The results predict that cytoskeletal disrupting drugs may be more potent in advanced stages of glaucoma.
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA.
authors.forename: Clayton T
authors.initials: CT
authors.lastname: McKee
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Wood
authors.forename: Nihar M
authors.initials: NM
authors.lastname: Shah
authors.forename: Marion E
authors.initials: ME
authors.lastname: Fischer
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Reilly
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Murphy
authors.forename: Paul
authors.initials: P
authors.lastname: Russell
mesh_terms: D001696:Biomechanical Phenomena / Q000187:drug effects; D055592:Biophysical Phenomena / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055119:Elastic Modulus / Q000187:drug effects; D005901:Glaucoma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D053778:Thiazolidines / Q000494:pharmacology / Q000627:therapeutic use*; D014129:Trabecular Meshwork / Q000187:drug effects / Q000473:pathology*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D053778:Thiazolidines; C037068:latrunculin B