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

Katherine J. Wert, Vinit B. Mahajan, Lijuan Zhang, Yuanqing Yan, Yao Li, Joaquin Tosi, Chun Wei Hsu, Takayuki Nagasaki, Kerstin M. Janisch, Maria B. Grant, Maryann Mahajan, Alexander G. Bassuk, Stephen H. Tsang

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article number16005
JournalSignal Transduction and Targeted Therapy
Volume1
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

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Hypoxia-Inducible Factor 1
Diabetic Retinopathy
Von Hippel-Lindau Tumor Suppressor Protein
Vitreous Hemorrhage
Ubiquitination
Iris
Retinal Detachment
Blindness
Glaucoma
Transcription Factors
Animal Models
Phenotype
Therapeutics
Proteins
Hypoxia

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

Cite this

Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy. / Wert, 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.; Tsang, Stephen H.

In: Signal Transduction and Targeted Therapy, Vol. 1, 16005, 01.01.2016.

Research output: Contribution to journalArticle

Wert, KJ, Mahajan, VB, Zhang, L, Yan, Y, Li, Y, Tosi, J, Hsu, CW, Nagasaki, T, Janisch, KM, Grant, MB, Mahajan, M, Bassuk, AG & Tsang, SH 2016, 'Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy', Signal Transduction and Targeted Therapy, vol. 1, 16005. https://doi.org/10.1038/sigtrans.2016.5
Wert, 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. ; Tsang, Stephen H. / Neuroretinal hypoxic signaling in a new preclinical murine model for proliferative diabetic retinopathy. In: Signal Transduction and Targeted Therapy. 2016 ; Vol. 1.
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