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Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy.

TitleNeuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy.
Publication TypeJournal Article
Year of Publication2016
AuthorsWert, Katherine J., Mahajan Vinit B., Zhang Lijuan, Yan Yuanqing, Li Yao, Tosi Joaquin, Hsu Chun Wei, Nagasaki Takayuki, Janisch Kerstin M., Grant Maria B., Mahajan Maryann, Bassuk Alexander G., and Tsang Stephen H.
JournalSignal Transduct Target Ther
Volume1
Date Published2016
ISSN2095-9907
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.

DOI10.1038/sigtrans.2016.5
Alternate JournalSignal Transduct Target Ther
PubMed ID27195131
PubMed Central IDPMC4868361
Grant ListR21 AG050437 / AG / NIA NIH HHS / United States
F32 CA196065 / CA / NCI NIH HHS / United States
R01 EY018213 / EY / NEI NIH HHS / United States
R01 EY016822 / EY / NEI NIH HHS / United States
R01 EY012601 / EY / NEI NIH HHS / United States
K08 EY020530 / EY / NEI NIH HHS / United States
R01 EY007739 / EY / NEI NIH HHS / United States
R01 EY026682 / EY / NEI NIH HHS / United States
T32 DK007647 / DK / NIDDK NIH HHS / United States
R01 EY024698 / EY / NEI NIH HHS / United States
P30 EY019007 / EY / NEI NIH HHS / United States
R01 EY025225 / EY / NEI NIH HHS / United States
P30 CA013696 / CA / NCI NIH HHS / United States
R01 HL110170 / HL / NHLBI NIH HHS / United States
R01 DK090730 / DK / NIDDK NIH HHS / United States
T32 EY013933 / EY / NEI NIH HHS / United States