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,glau...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 HIF1αfor ubiquitination.We found that the neuroretinal cells in these mice overexpressed HIF1αand 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.展开更多
基金This work was supported by the National Institute of Health Core(5P30EY019007)National Cancer Institute Core(5P30CA013696)and unrestricted funds from Research to Prevent Blindness+6 种基金New York,NY,USA.KJW was supported by the National Institute of Health(5T32EY013933 and 5T32DK007647-20)during these experiments and is currently supported by the National Cancer Institute(F32CA196065)SHT is a member of the RD-CURE Consortium and is supported by the Tistou and Charlotte Kerstan Foundation,the National Institute of Health(R01EY018213)the Research to Prevent Blindness Physician-Scientist Award,Association for Research in Vision and Ophthalmology Foundation,Macula Society,the Barbara and Donald Jonas Family Fund,the Schneeweiss Stem Cell Fund,New York State(C029572)the Foundation Fighting Blindness New York Regional Research Center Grant(C-NY05-0705-0312)the Joel Hoffman Fund,the Professor Gertrude Rothschild Stem Cell Foundation,and the Gebroe Family FoundationVBM is supported by NIH Grants K08EY020530,R01EY016822 and Research to Prevent Blindness,New York,NY,USAMBG is supported by R01EY07739,R01EY012601,R01HL110170 and R01DK090730.
文摘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 HIF1αfor ubiquitination.We found that the neuroretinal cells in these mice overexpressed HIF1αand 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.
