# Exploring the angiogenesis-to-fibrosis transition in ischemic retinopathies

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $372,397

## Abstract

Diabetic retinopathy (DR) and other forms of retinal ischemia are a leading cause of blindness in working age
adults. There is a need to identify the mechanisms that control the transition from angiogenesis to fibrosis in
these conditions. This would be a first step towards new therapies to address progressive vascular endothelial
damage that ultimately leads to pre-retinal fibrosis and traction detachment with poor visual and anatomic
outcomes.
To address this gap in our knowledge, we have designed a series of experiments that build logically on our
preliminary data, which shows evidence for endothelin-1 (ET-1) involvement in fibrovascular human surgical
membranes. We hypothesize that dysregulated endothelial ET-1 is particularly important in the pathogenesis of
ischemia-induced retinopathy and its complications.
To examine this hypothesis, we will study animal models that span the entire spectrum of retinal ischemia,
including streptozotocin (STZ)-induced diabetes and models of developmental ischemia- the oxygen induced
retinopathy (OIR, to replicate angiogenesis in ischemia) and the limited hyperoxia-induced proliferative
retinopathy (l-HIPR), which replicates the angiofibrotic end-stages of severe ischemia. We will use these
models to test the hypothesis that dysregulation of vascular endothelial cell-derived ET-1 is critically involved in
the promotion of vascular pathology, using an inducible, targeted vascular endothelial ET-1 knockout
transgenic mouse (ET-1Eko). In aim 1, we subject this ET-1Eko mouse to the STZ-induced diabetes and the
developmental models of ischemia to study the role of endothelial ET-1 dysregulation in angiogenesis and
fibrosis. In aim 2, we will cross the ET-1Eko with a transgenic reporter mouse model to focus on the endothelial-
to-mesenchymal transition in the retinal vessels and the surrounding pericytes, glia and neurons. Finally, in aim
3, we will focus on developing pharmacologic interventions geared towards ET-1 receptors to improve retinal
pathology in models of DR, ischemia- induced angiogenesis and fibrosis (OIR and l-HIPR), as a first step
towards translating our findings to the bedside.
The mechanistic experiments proposed herein will capitalize on the interdisciplinary expertise of the clinician-
scientist PI and her collaborators. Dr. Fawzi is a clinician-scientist retina surgeon with special expertise in non-
invasive retinal imaging, animal models of ischemia and retinal vascular diseases. Her co-investigator, Dr.
Schnaper is a clinician-scientist, pediatric nephrologist, who is a world expert in fibrogenic signaling. Finally,
the group also capitalizes on novel imaging technologies in Dr. Zhang’s lab at Northwestern University, another
collaborator.

## Key facts

- **NIH application ID:** 10400830
- **Project number:** 5R01EY030121-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Amani A Fawzi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $372,397
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10400830

## Citation

> US National Institutes of Health, RePORTER application 10400830, Exploring the angiogenesis-to-fibrosis transition in ischemic retinopathies (5R01EY030121-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10400830. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*