Journal
SIGNAL TRANSDUCTION AND TARGETED THERAPY
Volume 1, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sigtrans.2016.5
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Funding
- National Institute of Health Core [5P30EY019007]
- National Cancer Institute Core [5P30CA013696]
- Research to Prevent Blindness, New York, NY, USA
- National Institute of Health [R01EY018213, 5T32EY013933, 5T32DK007647-20]
- National Cancer Institute [F32CA196065]
- Tistou and Charlotte Kerstan Foundation
- Research to Prevent Blindness Physician-Scientist Award
- Association for Research in Vision and Ophthalmology Foundation
- Barbara and Donald Jonas Family Fund
- Schneeweiss Stem Cell Fund, New York State [C029572]
- Foundation Fighting Blindness New York Regional Research Center Grant [C-NY05-0705-0312]
- Joel Hoffman Fund
- Professor Gertrude Rothschild Stem Cell Foundation
- Gebroe Family Foundation
- NIH [K08EY020530, R01EY016822]
- Macula Society
- [R01EY07739]
- [R01EY012601]
- [R01HL110170]
- [R01DK090730]
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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 (HIF1 alpha). 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 HIF1 alpha for ubiquitination. We found that the neuroretinal cells in these mice overexpressed HIF1 alpha 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.
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