title: Identification of RUNX1 as a Mediator of Aberrant Retinal Angiogenesis.
abstract: Proliferative diabetic retinopathy (PDR) is a common cause of blindness in the developed world's working adult population and affects those with type 1 and type 2 diabetes. We identified Runt-related transcription factor 1 (RUNX1) as a gene upregulated in CD31+vascular endothelial cells obtained from human PDR fibrovascular membranes (FVMs) via transcriptomic analysis. In vitro studies using human retinal microvascular endothelial cells (HRMECs) showed increased RUNX1 RNA and protein expression in response to high glucose, whereas RUNX1 inhibition reduced HRMEC migration, proliferation, and tube formation. Immunohistochemical staining for RUNX1 showed reactivity in vessels of patient-derived FVMs and angiogenic tufts in the retina of mice with oxygen-induced retinopathy, suggesting that RUNX1 upregulation is a hallmark of aberrant retinal angiogenesis. Inhibition of RUNX1 activity with the Ro5-3335 small molecule resulted in a significant reduction of neovascular tufts in oxygen-induced retinopathy, supporting the feasibility of targeting RUNX1 in aberrant retinal angiogenesis.
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Lam
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Oh
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Lindsay L
authors.initials: LL
authors.lastname: Wong
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Dhanesh
authors.initials: D
authors.lastname: Amarnani
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Park-Windhol
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Angie V
authors.initials: AV
authors.lastname: Sanchez
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.|Universidad Pontificia Bolivariana, Medellin, Colombia.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cardona-Velez
authors.affiliation: C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA.
authors.forename: Declan
authors.initials: D
authors.lastname: McGuone
authors.affiliation: C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA.
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.affiliation: Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Dean
authors.initials: D
authors.lastname: Eliott
authors.affiliation: Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
authors.affiliation: Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Tave
authors.initials: T
authors.lastname: van Zyl
authors.affiliation: Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Lishuang
authors.initials: L
authors.lastname: Shen
authors.affiliation: Center for Personalized Medicine, Children's Hospital Los Angeles, Los Angeles, CA.
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Gai
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA joseph_arboleda@meei.harvard.edu leo_kim@meei.harvard.edu patricia_damore@meei.harvard.edu.|Department of Pathology, Harvard Medical School, Boston, MA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA joseph_arboleda@meei.harvard.edu leo_kim@meei.harvard.edu patricia_damore@meei.harvard.edu.|Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, Schepens Eye Research Institute/Massachusetts Eye and Ear, Harvard Medical School, Boston, MA joseph_arboleda@meei.harvard.edu leo_kim@meei.harvard.edu patricia_damore@meei.harvard.edu.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Arboleda-Velasquez
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008875:Middle Aged; D010100:Oxygen / Q000009:adverse effects; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000378:metabolism*; D015861:Retinal Neovascularization / Q000235:genetics* / Q000378:metabolism
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D012333:RNA, Messenger; C493728:RUNX1 protein, human; C493726:Runx1 protein, mouse; D005947:Glucose; D010100:Oxygen