title: Pro-fibrotic pathway activation in trabecular meshwork and lamina cribrosa is the main driving force of glaucoma.
abstract: While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFβ observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.
authors.affiliation: a Insilico Medicine, Inc., ETC, Johns Hopkins University , Baltimore , MD , USA.|b The Biogerontology Research Foundation , London , UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Zhavoronkov
authors.affiliation: e Johns Hopkins University , Department of Otolaryngology-Head and Neck Surgery.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Izumchenko
authors.affiliation: c Vision Genomics, LLC , Washington, DC , USA.|d Epigenetics Laboratory, Howard University , Washington, DC , USA.
authors.forename: Riya R
authors.initials: RR
authors.lastname: Kanherkar
authors.affiliation: c Vision Genomics, LLC , Washington, DC , USA.
authors.forename: Mahder
authors.initials: M
authors.lastname: Teka
authors.affiliation: f Boston University , Boston , MA , USA.|g Retrotope, Inc ; Los Altos Hills , CA , USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Cantor
authors.affiliation: d Epigenetics Laboratory, Howard University , Washington, DC , USA.
authors.forename: Kebreten
authors.initials: K
authors.lastname: Manaye
authors.affiliation: c Vision Genomics, LLC , Washington, DC , USA.
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
authors.affiliation: h BioTime, Inc. , Alameda , CA , USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: West
authors.affiliation: a Insilico Medicine, Inc., ETC, Johns Hopkins University , Baltimore , MD , USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Makarev
authors.affiliation: c Vision Genomics, LLC , Washington, DC , USA.|d Epigenetics Laboratory, Howard University , Washington, DC , USA.
authors.forename: Antonei Benjamin
authors.initials: AB
authors.lastname: Csoka
mesh_terms: D001082:Aqueous Humor / Q000378:metabolism; D019295:Computational Biology; D066264:Datasets as Topic; D016326:Extracellular Matrix Proteins / Q000235:genetics* / Q000378:metabolism; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D005902:Glaucoma, Open-Angle / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D006801:Humans; D007429:Intraocular Pressure; D046228:Microarray Analysis; D058977:Molecular Sequence Annotation; D058990:Molecular Targeted Therapy; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D012590:Sclera / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D014129:Trabecular Meshwork / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
chemical_list: D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta
keywords: POAG; TGFβ; fibrosis; glaucoma; lamina cribrosa; trabecular meshwork