title: Cochlin, intraocular pressure regulation and mechanosensing.
abstract: Fluid shear modulates many biological properties. How shear mechanosensing occurs in the extracellular matrix (ECM) and is transduced into cytoskeletal change remains unknown. Cochlin is an ECM protein of unknown function. Our investigation using a comprehensive spectrum of cutting-edge techniques has resulted in following major findings: (1) over-expression and down-regulation of cochlin increase and decrease intraocular pressure (IOP), respectively. The overexpression was achieved in DBA/2J-Gpnmb(+)/SjJ using lentiviral vectors, down-regulation was achieved in glaucomatous DBA/2J mice using targeted disruption (cochlin-null mice) and also using lentiviral vector mediated shRNA against cochlin coding region; (2) reintroduction of cochlin in cochlin-null mice increases IOP; (3) injection of exogenous cochlin also increased IOP; (4) increasing perfusion rates increased cochlin multimerization, which reduced the rate of cochlin proteolysis by trypsin and proteinase K; The cochlin multimerization in response to shear stress suggests its potential mechanosensing. Taken together with previous studies, we show cochlin is involved in regulation of intraocular pressure in DBA/2J potentially through mechanosensing of the shear stress.
authors.affiliation: Bascom Palmer Eye Institute, University of Miami, Miami, Florida, United States of America.
authors.forename: Manik
authors.initials: M
authors.lastname: Goel
authors.forename: Adam E
authors.initials: AE
authors.lastname: Sienkiewicz
authors.forename: Renata
authors.initials: R
authors.lastname: Picciani
authors.forename: Jianhua
authors.initials: J
authors.lastname: Wang
authors.forename: Richard K
authors.initials: RK
authors.lastname: Lee
authors.forename: Sanjoy K
authors.initials: SK
authors.lastname: Bhattacharya
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015153:Blotting, Western; D002102:Cadaver; D002478:Cells, Cultured; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D005123:Eye / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007429:Intraocular Pressure; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008875:Middle Aged; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D055503:Protein Multimerization; D034741:RNA, Small Interfering / Q000235:genetics; D033081:Shear Strength; D014129:Trabecular Meshwork / Q000378:metabolism / Q000473:pathology*
chemical_list: C110668:COCH protein, human; C491729:Coch protein, mouse; D016326:Extracellular Matrix Proteins; D034741:RNA, Small Interfering