Ongoing Research in the Kazlauskas Lab
After a multi-decade period in academia, Dr. Kazlauskas closed his research lab at the Schepens Eye Research Institute/Harvard Medical School to transition to F. Hofmann-La Roche in Basel, Switzerland, where he joined the Department of Ophthalmology and contributed to the drug development process. In 2017 Dr. Kazlauskas re-started academic research focused on preventing patients with diabetes from developing diabetic retinopathy, and improving current approaches to treat this condition.
Pharmacosignaling in PDR
The goal of this project is to elucidate the molecular basis of anti-VEGF’s benefit in patients with proliferative diabetic retinopathy (PDR). The clinical observation that neutralizing VEGF reduces retinal edema and improves visual acuity in most patients, motivates us to investigate the underlying mechanism of this phenomenon. To this end we are first identifying changes in gene expression and signaling events that are associated with anti-VEGF treatment in patients. The next step is to determine which of these changes are responsible for the therapeutic benefit. These discoveries will guide the design of alternative therapies for patients that do not fully benefit from existing anti-VEGFs. Furthermore, we will develop biomarkers that will improve our ability to diagnose susceptibility, monitor both disease progression, and the efficacy of intervention.
Preventing diabetic retinopathy
The delay in development of diabetic retinopathy (DR) in most patients with diabetes (DM) indicates the existence of an endogenous system that protects the retina from DM-induced damage (Fig 1). We posit that failure of this system is a prerequisite for DR, and its persistence underlies the extended delay (> 50 years) of DR in medalists, which is unrelated to glycemic control. The nature of the system that protects from DR has not been investigated at least in part due to the paucity of experimental systems that model it. Identifying the molecular mediators of this endogenous system along with their mechanism of action will enable development of novel approaches to prevent DR, which would be of substantial benefit in light of the ineffectiveness of currently available prophylactic options.
We developed novel in vitro and ex vivo assays to model the endogenous system that protects the retinal vasculature from DM-driven damage. Using these assays we discovered that prolonged exposure of primary human retinal endothelial cells (HRECs) to hyperglycemia (HG) triggers adaptation, which results in resistance to the damaging effects of HG. Furthermore, the underlying mechanism of adaption involves a shift in metabolism and improved mitochondrial functionality. Importantly, key features of this in vitro phenomenon appear to occur in the retinal vessels of mice. We are continuing to investigate the endogenous system that protects the retinal vasculature from DM-driven damage.