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.
This proposal aims to study the process of retinal vascular damage that leads to retinal blindness from lack of oxygen and nutrients. The experiments use a range of mouse models that replicate the different stages of human disease, allowing the team to study specific markers that promote scar formation. Success of this proposal will lead to the development of non-invasive therapies that can prevent advanced scar tissue formation in the retina, along with their devastating and blinding complications.
