title: Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy.
abstract: Diabetic retinopathy (DR) affects approximately one-third of diabetic patients and, if left untreated, progresses to proliferative DR (PDR) with associated vitreous hemorrhage, retinal detachment, iris neovascularization, glaucoma and irreversible blindness. In vitreous samples of human patients with PDR, we found elevated levels of hypoxia inducible factor 1 alpha (HIF1α). HIFs are transcription factors that promote hypoxia adaptation and have important functional roles in a wide range of ischemic and inflammatory diseases. To recreate the human PDR phenotype for a preclinical animal model, we generated a mouse with neuroretinal-specific loss of the von Hippel Lindau tumor suppressor protein, a protein that targets HIF1α for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1α and developed severe, irreversible ischemic retinopathy that has features of human PDR. Rapid progression of retinopathy in these mutant mice should facilitate the evaluation of therapeutic agents for ischemic and inflammatory blinding disorders. In addition, this model system can be used to manipulate the modulation of the hypoxia signaling pathways, for the treatment of non-ocular ischemic and inflammatory disorders.
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA; Institute of Human Nutrition, Columbia University, New York, NY, USA.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Wert
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; Omics Laboratory, University of Iowa, Iowa City, IA, USA.
authors.forename: Vinit B
authors.initials: VB
authors.lastname: Mahajan
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Li
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Tosi
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA.
authors.forename: Chun Wei
authors.initials: CW
authors.lastname: Hsu
authors.affiliation: Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nagasaki
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA.
authors.forename: Kerstin M
authors.initials: KM
authors.lastname: Janisch
authors.affiliation: Eugene and Marilyn Glick Eye Institute, Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Grant
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, USA; Omics Laboratory, University of Iowa, Iowa City, IA, USA.
authors.forename: MaryAnn
authors.initials: M
authors.lastname: Mahajan
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Bassuk
authors.affiliation: Bernard and Shirlee Brown Glaucoma Laboratory and Barbara & Donald Jonas Laboratory of Regenerative Medicine, Columbia University, New York, NY, USA; Edward S. Harkness Eye Institute, Columbia University, New York, NY, USA; Institute of Human Nutrition, Columbia University, New York, NY, USA; New York Presbyterian Hospital/Columbia University Medical Center, New York, NY, USA; Department of Pathology and Cellular Biology, Columbia University, New York, NY, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Tsang