Michael Rogers

The Rogers lab works to identify new targets and therapeutics for angiogenesis-dependent disease.  A key element of this work is our efforts to understand the role of Capillary Morphogenesis Gene 2 (CMG2) in angiogenesis and the signaling pathway downstream of natural ligand engagement.  CMG2 is an extracellular matrix receptor with a unique and poorly characterized intracellular domain.  CMG2 has been most studied as the high-affinity anthrax toxin receptor, but its physiological function is less well understood.  In the context of corneal neovascularization, we have found that knocking out or inhibiting CMG2 with protein or small-molecule inhibitors profoundly reduces bFGF- or VEGF-induced angiogenesis.  In endothelial cells, these same inhibitors disrupt chemotaxis, not by reducing adhesion or migration rate, but by randomizing the direction cells move.  Because the CMG2 intracellular domain lacks apparent signaling motifs, we infer that CMG2 signaling is mediated by differential protein-protein interaction.  Therefore, we are currently using proximity proteomics techniques to identify proteins whose interaction differs between active and inhibited CMG2, with the goal of elucidating the downstream angiogenesis-regulating signaling pathway.  Given the potent effect that CMG2 inhibitors have in vivo, we anticipate that these molecules will include additional targets for antiangiogenic therapy in corneal neovascularization, cancer, and other angiogenesis-dependent diseases.

Among the other diseases that the Rogers lab studies is endometriosis.  When compared to eutopic endometrium, endometriosis lesions dramatically upregulate CMG2, likely as a result of local tissue hypoxia.  To better understand endometriosis pathophysiology, we have developed the first validated mouse model of endometriosis-associated pain.  In this model, we and others have found that CMG2 inhibitors reduce lesion burden and pain.  We are currently working to elucidate the molecular and cellular mechanisms underlying this effect, with the goal of putting together a development pipeline for new CMG2-directed endometriosis therapeutics.  We are also working to identify additional pathways that can be leveraged to treat the disease.  Such efforts currently include work to identify the molecular targets for natural products that we have discovered dramatically decrease pain and lesion growth in our model.  We are also performing whole-genome CRISPR screens to identify liabilities induced by cancer-associated mutations, which are common in the epithelium of endometriosis lesions.  Altogether, our lab works to generate insights into the pathophysiology of endometriosis, corneal neovascularization, and tumor angiogenesis that can be leveraged to enable the development of new disease therapies.