Our Research
The Corson Lab applies chemical biology to problems in vision science. We use a wide variety of techniques, including high-throughput compound screening, novel compound development, and biochemical approaches to compound mechanism of action. The lab also applies more traditional techniques, including tissue culture, expression analyses, in vivo modeling, and molecular biology. We are developing small molecules as probes and therapeutic leads for the common, blinding afflictions of neovascular age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity, all of which are associated with abnormal excess blood vessel growth in the eye (neovascularization). We are also investigating the basic biology of, and potential therapeutic approaches for, the pediatric ocular tumor retinoblastoma, which is responsible for one percent of childhood cancer deaths and five percent of childhood blindness. Some of our ongoing projects are highlighted below.
Novel Antiangiogenic Compounds
There is a pressing need for novel small molecule drugs to block pathological neovascularization in the eye. In collaboration with Seung-Yong Seo of Gachon University and Dulcie Mulholland of the University of Surrey, we are producing novel antiangiogenic compounds based on natural products. We previously synthesized cremastranone, an antiangiogenic natural product, and developed a novel isomer for this compound with antiangiogenic activity against retinal endothelial cells. We undertook a cell-based structure-activity relationship study of this class of compounds and developed a new analog, SH-11037, with promising antiangiogenic activity in vitro and in vivo.
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The Role of Heme Synthesis in Angiogenesis
In addition to the testing of novel compounds in various angiogenesis models, we are interested in discovering how these compounds work at the molecular level, by using chemical proteomics approaches. Current NEI R01 grant-funded work focuses on the heme synthesis enzyme ferrochelatase, which is a target of cremastranone and which we have shown is important for angiogenesis in vitro and in vivo. Griseofulvin, an old anti fungal drug that inhibits ferrochelatase as an off-target effect, can be repurposed as an antiangiogenic agent. In collaboration with Yoon Yeo at Purdue University, we have developed and validated sustained-release formulations of this drug for intraocular delivery. In addition, with Prof. Seo we developed the first drug-like ferrochelatase inhibitor, a powerful tool for further exploration of this enzymes role in angiogenesis.
Ref-1 as a Mediator of Ocular Disease
Redox transcriptional regulator APE1/Ref-1 acts as a signaling nexus for inflammatory and proangiogenic stimuli. Working with Mark Kelley at Indiana University School of Medicine, we are characterizing the mechanisms by which Ref-1 promotes angiogenesis, and exploring novel Ref-1 inhibitors such as APX3330 and APX2009 for their therapeutic effect in ocular disease models.
