My laboratory is interested in the molecular mechanisms governing the formation and function of the blood-brain barrier. We have identified key molecules and previously unappreciated mechanism that controls the blood-brain barrier function. These information will be essential for drug delivery to the central nervous system to treat neurological diseases and brain tumors.
We also interested in the role of a newly identified angiogenesis regulator, the traditional axon guidance cues, in vascular development and angiogenesis in cancer. To that end we have focused on the largest family of repulsive guidance cue, the semaphorins. Specifically on the class 3 secreted semaphorins and their receptors of Neuropiins and plexins. The study of semaphorin 3E and its receptor Plexin-D1 function in the mouse retina vasculature has revealed an unexpected role as a negative feedback regulator of VEGF via a cross-talk to Dll4-Notch pathway. Given the significant role of VEGF in cancer angiogenesis, the discovery of Sema3E-Pleixn-D1 signaling as an important regulator of VEGF suggest that developing agents targeting Sema3E-Pleixn-D1 signaling pathways along or in combination with anti-VEGF may be a new therapeutic strategy. Moreover, we have developed a novel image-based genomewide RNAi screen to identify Sema3E-Pleixn-D1 downstream signaling component in endothelial cells. We have identified and validated several candidate genes. One of them is a Rac1 regulator. The characterization of the signaling pathway from Sema3E-Plexin-D1 to Rac1 activity changes and subsequent cytoskeleton changes shed new light on our understanding of how Sema3E-Plexin-D1 signal transduced in the endothelial cells. Given the important role of Sema3E-Plexin-D1 in angiogenesis and tumorgenesis, the identification of novel downstream signaling molecules will not only provide the building blocks for understanding their function, but also provide potential drug target for cancer therapy.