Vascular clock disruption in diabetes: Implications for diabetic retinopathy

With the impending rise of diabetes, approximately 224 million people worldwide will have some form of diabetic retinopathy (DR) by 2045. No cures are available, and treatments are only appropriate for the late stages when loss of vision is imminent. There is an urgent need to better understand its pathobiology to develop new therapies and prevention strategies.

Lifestyle changes are often recommended to prevent DR. In this context, the circadian system, our internal biological clock, plays a vital role in integrating environmental cues to regulate many genes and processes. This system has evolved to align our physiology with the Earth's daily rotation, aiding survival.

At the molecular level, it optimizes cellular functions, including in endothelial cells. Clock disruption in endothelial cells of the retina has been described in patients with diabetes. As we recognize its significance in endothelial cell function, it becomes increasingly crucial to investigate the role of the circadian clock in DR, as it may regulate key processes in the disease.

This project aims to understand how circadian disruption in endothelial cells contributes to DR progression. We hypothesize that disruption of the endothelial cell clock due to diabetes plays a significant role in affecting the functioning of endothelial cells in DR. This disruption weakens their ability to withstand diabetic-related damage, leading to poorer DR outcomes and reduced treatment efficacy.

In Aim 1, we will establish that endothelial cells obtained from patients across different stages of DR stages display disrupted clocks that correspond to the seriousness of the disease. We will make a comparative analysis of circadian rhythms in endothelial cells derived from induced pluripotent stem cells sourced from both healthy individuals and diabetic patients representing a spectrum of DR stages.

Using this approach, we aim to establish a clear connection between vascular clock disruption and disease severity while also delving into the mechanisms by which diabetes interferes with the vascular clock.

In Aim 2, we will investigate the role of the endothelial cell clock in the progression of DR. We will employ both in vivo and in vitro methods, to assess the role of BMAL1, a core clock protein, in driving the disease. We will use genetically modified mice lacking circadian rhythmicity exclusively in their vessels, induce diabetes in them to simulate elevated blood glucose levels and the onset of DR, and we will evaluate the onset of critical processes in human DR.

These include vessel survival, permeability, leukocyte adhesion, and pathological neovascularization. In vitro genetic and chemical approaches with chronomodulators will be used to gain mechanistic insights into how clock disruption influences these processes, potentially leading to the discovery of novel therapeutic targets for the treatment of DR.

Establishing a link between clock disruption and DR progression may enable the use of patient-derived endothelial cells to predict individuals at risk of worsening DR. Monitoring vascular clock disruption in these cells can also guide the selection of appropriate chronomodulators to restore disrupted rhythms, enhancing disease management.

In an era marked by a rising prevalence of diabetes and its complications, this research holds the potential to significantly improve the lives of millions through a deeper understanding of the interactions of a molecular system assaulted daily by our modern lifestyles on the progression of vascular complications arising from diabetes.