# Divergent Roles for Hypoxia-Inducible Factor-1 and -2 in Ischemic Retinal Disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $530,319

## Abstract

SUMMARY.
 Diabetes accounts for 10% of healthcare spending in the United States. A growing portion of this
cost is spent on treatments for diabetic eye disease, the most common ischemic retinopathy (IR) and
the leading cause of blindness among working-age adults in the developed world. Hypoxia-inducible
factors (HIFs) are transcriptional regulators that control the expression of the hyperpermeabilty and
angiogenic mediators that promote the development of macular edema (ME) and retinal
neovascularization (NV) in patients with IRs. Therapies targeting one HIF-regulated angiogenic
mediator, vascular endothelial growth factor (VEGF), are the gold standard for treating ME in IR
patients, and have more recently emerged as effective treatments for NV in diabetic patients. However,
less than half of treated patients respond adequately to anti-VEGF therapies, supporting a role for other
HIF-regulated angiogenic factors in the development of NV. HIFs are composed of an exquisitely
oxygen-sensitive  subunit and a ubiquitously-expressed  subunit. HIF-1α, first HIF  subunit isoform
to be identified, has been shown to play an important role in retinal vascular disease. Two other HIF
isoforms, HIF-2α and HIF-3α, have subsequently been reported; while HIF-2α is closely related to HIF-
1α and also activates hypoxia-inducible gene transcription, HIF-3α is more distantly related and can
either activate or repress expression of HIF target genes. The relative contribution of HIF-1 vs HIF-2 to
the expression of genes that regulate the initiation, promotion, and progression of NV is not known.
Similarly, the neuroprotective role of HIFs – and HIF-regulated gene products – following hypoxic injury
to the vulnerable neurosensory retina remains poorly understood. We hypothesize that accumulation
of specific HIFs in different cells at precise stages following hypoxic injury determines the HIF-
dependent gene expression signature in hypoxic retinal cells; this cell-specific, time-dependent
gene signature determines the “pathologic” vs “protective” role(s) of HIFs. To address this
hypothesis, we propose to determine the contribution of HIFs to the initiation, promotion, and
progression of NV by Müller cells in IRs (SA1); determine the contribution of HIFs to RGC survival
following hypoxic injury in IRs (SA2); and determine the contribution of HIF-2 regulation of PAI-1 to the
development of retinal NV in IRs (SA3). Successful completion of these studies will provide insight into
the pathologic vs protective role(s) of HIF-1 and HIF-2 in different cells at different stages following
hypoxic injury in patients with IRs, and will identify novel therapeutic approaches for preventing or
treating patients with these vision threatening disease.

## Key facts

- **NIH application ID:** 9882284
- **Project number:** 5R01EY029750-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Akrit Singh Sodhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $530,319
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882284

## Citation

> US National Institutes of Health, RePORTER application 9882284, Divergent Roles for Hypoxia-Inducible Factor-1 and -2 in Ischemic Retinal Disease (5R01EY029750-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9882284. Licensed CC0.

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