Rajagopal Lab
Rithwick Rajagopal, MD, PhD, Assistant Professor, Ophthalmology and Visual Sciences
At the Rajagopal Retina Research Laboratory, we are driven by the mission to advance our understanding of the underlying mechanisms responsible for common retinal diseases. Our research lies at the intersection of ophthalmology, neuroscience, and metabolic disorders, where we strive to uncover new pathways and therapeutic strategies to combat vision loss caused by metabolic diseases, genetic changes, and by age.
Local and Systemic Lipid Metabolism in the Maintenance of Retinal Health
Our lab identified that cellular pathways responsible for building complex lipids from simple precursors are crucial for the maintenance of retinal health. Disruption of the key enzyme in this lipogenic pathway – Fatty Acid Synthase (FAS) – results in profound postnatal retinal degeneration. Moreover, diseases such as diabetic retinopathy appear to stem from dysregulated de novo lipogenesis in photoreceptors.
Building on this observation, our lab went on to demonstrate that key upstream molecules that respond to nutritional signals – including the Adenosine Monophosphate Activated Kinase (AMPK) – are grossly dysregulated in diabetes. The defect appears to be driven by elevated blood glucose levels characteristic of diabetes, as the retina, like other neural tissues, primarily relies on glucose for energy. Strikingly, increasing the energy demands of photoreceptors—a class of neurons with one of the highest metabolic rates in the body—can serve as a physiological outlet for excess energy in the diabetic retina, potentially preventing disease. We demonstrated this using pharmacologic visual cycle inhibition and prolonged dark adaptation, both of which increase retinal ATP demand and reduce the severity of experimental diabetic retinopathy. We are now working on several follow up lines of investigation. First, we are interested in understanding the impact of these cellular and biochemical changes on retinal blood flow and photoreceptor function. Second, we study diabetes-induced changes to retinal lipid metabolism and lipid-dependent cellular and molecular processes. Finally, we are surveying aspects of systemic lipid metabolism that impact the health of the retina, with findings relevant to diabetic retinopathy, inherited retinopathies, and age-related retinal disease.
In these studies, we use techniques such as lipid mass spectrometry and high resolution retinal imaging to identify changes in retinal lipid composition in diabetes. In a related set of studies, we are investigating mechanisms of action of a lipid-lowering agent, fenofibrate, which may reduce the severity of DR in patients. The protective effects of this drug appear to be independent of its role in activating its canonical receptor – the peroxisome proliferator-activated receptor alpha (PPARα) – in the retina itself. Rather, our preliminary evidence suggests that systemically-induced factors mediate the effects of fenofibrate on the diabetic retina. To investigate this, we use cell cultures, proteomics, and targeted genetic modifications in animal models. In addition, we are participating in a national multi-center clinical trial aimed at proving whether fenofibrate does in fact reduce diabetic retinopathy severity.
Retinal Neurovascular Coupling in Health and Disease
Neuronal activity is a major determinant of its vascular supply, operating through a process known as neurovascular coupling. This project explores the relationship between neuroretinal metabolism and neurovascular coupling dynamics in the inner retinal blood supply. Our lab investigates these changes using mouse models of retinal disease as well as patient studies, making our research highly translational. By analyzing responses, we aim to identify distinct vascular patterns that may serve as predictive markers for the onset and severity of diseases such as diabetic retinopathy. This approach could deepen our understanding of retinal vascular dynamics and enhance diagnostic and monitoring strategies for retinal diseases.
