Signal transduction and gene regulatory mechanisms in vascular biology
Molecular Mechanisms of Angiogenesis
The Hla laboratory has been interested in defining the molecular mechanisms of the angiogenic process, whereby endothelial cells from pre-existing blood vessels sprout, migrate and undergo morphogenesis to form new vascular channels. In the 1990s, we identified the sphingosine 1-phosphate receptor (S1P1) and cyclooxygenase-2 (COX)-2 as key angiogenic response genes. Our work has helped establish the concept that COX-2 enzyme function is important in cancer progression and angiogenesis. In addition, we now know that S1P signals via its G protein-coupled S1P receptors and regulate vascular and immune systems in normal physiology and disease.
Current studies are focused on dissecting how S1P signaling impacts endothelial and immune cells to regulate angiogenesis and vascular disease. We use cell culture systems to define mechanisms and genetic mouse models to test the physiological relevance of our mechanistic findings. Current questions include how S1P receptors regulate vascular patterning events, whether subcellular trafficking and ubiquitinylation mechanisms of the receptor are important in S1P signaling, how gradients of S1P allow retention and/or trafficking of hematopoietic cells in specific tissue locales and how specific S1P receptors regulate vascular inflammation and atherosclerosis.
Post-transcriptional RNA Regulatory Mechanisms in Vascular and Stem Cell Biology
Our recent work on the RNA binding protein HuR (a.k.a. ELAV1) suggests that it is essential for progenitor cell survival in hematopoietic and intestinal systems. HuR regulates the p53 pathway in progenitor cells by post-transcriptional regulation of the upstream regulator, Mdm-2, an E3 ubiquitin ligase for the tumor suppressor p53. In the absence of HuR, p53 is induced and progenitor cell apoptosis ensues. In addition, HuR regulates the inflammatory process in differentiated cells of myeloid and vascular lineages. We are interested in the question of how this RNA binding protein interacts with small RNAs (e.g. miRNA) and influence key regulatory processes during angiogenesis, vascular maturation and inflammatory vascular disease such as atherosclerosis.