Ongoing Research in the Kazlauskas Lab
The overall goal of the Kazlauskas Lab is to elucidate the effect of diabetes (DM) on the retinal vasculature. The resulting conceptual advances will guide development of new therapeutic approaches to prevent patients with DM from developing diabetic retinopathy (DR), and improve current options to treat patients who have already developed DR. The two areas of research in the Kazlauskas Lab are summarized below; please see our recent publications for additional information:
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. We are focusing on VEGF- and anti-VEGF-regulated changes in gene expression, which are required to persistently alter the permeability of the retinal vasculature. To this end we use both in vitro models, and pathological blood vessels isolated from patients with PDR. We seek to identify the molecular governors of chronic leakage. Such information will enable design of alternatives to anti-VEGFs, as well as new biomarkers to improve our ability to diagnose susceptibility, monitor disease progression and the efficacy of intervention.
Protection from diabetic retinopathy (DR)
The delay in development of site-threatening DR in most patients with DM indicates the existence of an endogenous system that protects the retina from DM-induced damage. Just like patients, manifestation of DR in experimental animals is delayed from the onset of DM. We recently reported that this delay in mice was associated with increased retinal expression of antioxidative defense genes, as well as resistance of the retinal vasculature to oxidative stress-induced death. Protection was transient; it waned as the duration of DM was prolonged and DR developed. To investigate the mechanism of protection we used primary human retinal endothelial cells that tolerate exposure to high glucose by undergo hyperglycemia-induced mitochondrial adaptation (HIMA), which involves enhance mitophagy and improved mitochondrial functionality. Our ongoing studies seek to elucidate how DM/hyperglycemia trigger protection and what causes its loss.