David Antonetti, Ph.D., and Laura González-González, Ph.D.
The Molecular Physiology of the Blood-Retinal Barrier For the retina to do its job to help the brain convert light into vision, it requires a well-regulated metabolic environment. The blood-retinal barrier (BRB) is a structure of tightly joined cells that protect that environment, allowing nutrients in while keeping potentially damaging substances out. A buildup of vascular endothelial growth factor (VEGF) in the retina damages the BRB, making it more permeable. This leads to fluid buildup, much like a bruise after a hard bump. VEGF-induced retinal injury is linked to blinding eye diseases like diabetic retinopathy (DR). Understanding the molecular physiology of the BRB is a central focus in the lab of Kellogg investigator David Antonetti, Ph.D. He has received NIH R01 grant support for the following new studies: The role of Norrin in BRB Regeneration The Antonetti lab has worked for many years to understand how VEGF contributes to loss of the BRB. Current therapies blocking VEGF action have proven invaluable in the clinic. Now, Dr. Antonetti will serve as Principal Investigator on a project aimed at exploring the possibility of regenerating the BRB in diabetic retinopathy. Specifically, he is exploring whether the cytokine norrin may play a role in BRB regeneration. Norrin has already been shown to play a role in the development of the BRB. Building on that, the Antonetti lab has demonstrated in animal models that norrin can help restore the barrier properties of retinal blood vessels after they are weakened by diabetes. 10
“Loss of norrin signaling may be as important as increased VEGF action in diabetic retinopathy,” he says. “We have already demonstrated that norrin acts to restore the BRB, helping the diabetes-injured retina recover function. And we have found new pathways that cells use to build the BRB. In all, this research supports prioritizing norrin as a therapeutic target.” The Role of Heme in Retinal Vascular Development Dr. Antonetti will collaborate on a separate initiative arising from studying the genes expressed in retinal blood vessels—in particular, the gene FLCVR2. This project will explore a completely novel hypothesis, that FLCVR2 plays a role in brain and retinal blood vessel growth by transporting a critical molecule — heme —into developing cells. Heme is best known as a component of hemoglobin, where it binds with the iron to carry oxygen in the bloodstream. But that’s not heme’s only function. “In cell biology, heme is a real multitasker,” says Dr. Antonetti. “It’s a co-factor in several key reactions in cells. And remarkably, it appears to act as a signaling molecule in the regulation of blood vessel growth in the BRB.” As Dr. Antonetti was connecting the dots between heme and blood vessel growth in the BRB at Michigan, Thomas Arnold, M.D., was studying the role of the same transporter in his neonatal brain research at the University of California, San Francisco. The two laboratories have merged their efforts, with Dr. Arnold and Dr. Antonetti as Co-Principal Investigators on the resulting R01 project grant. “It’s really a brand new way to think about blood vessel development,” Dr. Antonetti says. “We hope it will lead to new ways to counter the out-of-control blood vessel growth that fuels blinding eye diseases.”
