Understanding the Role of the Vascular Clock in Diabetic Retinopathy

Diabetic retinopathy (DR) is a leading cause of vision loss, characterized by retinal vascular damage and neovascularization. This project seeks to understand the role of the vascular circadian clock in endothelial cell (EC) function and its impact on DR progression. Vascular cells, including ECs, possess a circadian clock that coordinates key biological processes, but diabetes disrupts these rhythms, potentially exacerbating retinal vascular dysfunction. The project aims to investigate how disrupted circadian rhythms affect endothelial survival, vessel permeability, leukocyte adhesion, and pathological angiogenesis in DR. Using both in vivo mouse models (e.g., STZ-induced diabetes and oxygen-induced retinopathy) and in vitro human retinal endothelial cell (HREC) models, the project will address four key objectives: 1. EC Survival under diabetic stress 2. Vessel Permeability, focusing on the blood-retina barrier. 3. Leukocyte Adhesion, testing clock-regulated adhesion molecules. 4. Pathological Angiogenesis in models of neovascularization. Preliminary data suggest that circadian disruption accelerates EC dysfunction, suggesting therapeutic potential for targeting the vascular clock in DR. This project offers a unique opportunity to explore circadian biology in retinal diseases and develop innovative therapeutics for DR treatment.

Diabetic retinopathy (DR) is the leading cause of visual impairment among working-age adults in industrialized countries, despite advancements in diabetes management. DR primarily affects the retina’s blood vessels, leading to leakage, oxygen deprivation, and abnormal vessel growth, ultimately resulting in blindness. The circadian clock, a molecular timekeeping system, plays a crucial role in regulating vascular functions. In endothelial cells (ECs), the circadian clock ensures the synchronization of vital processes with the daily light/dark cycle. However, diabetes disrupts these circadian rhythms, potentially contributing to DR development.

The circadian clock regulates essential aspects of endothelial cell biology, including survival, angiogenesis, permeability, and leukocyte adhesion. Disruption of this clock, particularly through the deletion of Bmal-1, impairs EC function and contributes to retinal ischemic injury and pathological angiogenesis. Furthermore, the circadian clock is crucial for maintaining the blood-retinal barrier (BRB), and its disruption may contribute to diabetic macular oedema (DMO).

Aims and Hypothesis:

This project aims to investigate the role of the vascular clock in DR, particularly how its disruption accelerates disease progression. The hypothesis the candidate will be testing is that disruption of the vascular circadian clock accelerates diabetic retinopathy. Using both in vivo and in vitro models, the project will examine how the endothelial circadian clock influences EC survival, vessel permeability, leukocyte adhesion, and pathological angiogenesis—all key mechanisms in DR progression.

Objectives:

1. To investigate the role of the vascular clock in EC survival during early-stage DR using diabetic rodent models and human retinal endothelial cells (HRECs).

2. To evaluate whether the circadian clock regulates blood-retina barrier integrity and vessel permeability in vivo using STZ-induced diabetic mice and in vitro using HRECs.

3. To investigate how circadian rhythms affect leukocyte adhesion and infiltration in DR. The role of adhesion molecules in endothelial-leukocyte interactions will be examined both in vivo and in vitro.

4. To explore the role of the vascular clock in pathological angiogenesis such as occurring in proliferative diabetic retinopathy (PDR) using the oxygen-induced retinopathy (OIR) model, and in vitro assays to study vessel formation and neovascularization.

The PhD student will work alongside two postdoctoral researchers and an animal technician within the Wellcome-Wolfson Institute for Experimental Medicine (WWIEM), in a collaborative environment with focus on vascular and vision research. This collaborative environment, shared resources, and expertise in diabetic retinopathy will ensure the success of the project.

This project could offer new therapeutic strategies to target the vascular clock, potentially leading to better treatments for both early and advanced stages of DR. The results will be published in peer-reviewed journals and presented at conferences, contributing significantly to our understanding of endothelial circadian rhythms in diabetic vascular diseases.