PRINCIPAL INVESTIGATOR: Luyuan Li, PhD Associate Professor of Pathology Office: 5117 Centre Ave HCC-G12C Pittsburgh, PA 15232 Email: lil@upmc.edu Tel: 412-623-1118 Fax: 412-623-1217    Mission Statement: Neovascularization, the formation of new capillary vessels from existing vasculature, is essential to the development of many important disease conditions, including cancer, rheumatoid arthritis, and diabetic retinopathy. The main goal of our research is of two-fold: to understand the molecular mechanism of angiogenesis and, based on such understanding, to develop therapeutic agents targeting disorders involving neo-vascularization. RESEARCH: My lab is interested in the molecular mechanisms of vascular homeostasis. There are two major projects. One focuses on an endothelial cell-specific gene that we discovered a few years ago and named vascular endothelial growth inhibitor, VEGI, known also as TNFSF15. Our findings indicate that VEGI modulates the cell growth cycle and death of endothelial cells. Systemic administration of recombinant VEGI in animal models leads to eradication of tumor endothelial cells and inhibition of tumor growth. In addition, VEGI may play a role in the regulation of the function of dendritic cells, and the differentiation of endothelial progenitor cells from hematopoietic stem cells. We are studying the mechanism of VEGI action and the potential of this unique cytokine as an anticancer therapeutic agent. The other project focuses on human rhomboid family-1, RHBDF1, also a novel gene that we discovered recently. We found that RHBDF1 is critically involved in the activation of the oncogene epidermal growth factor receptor, EGFR. Silencing RHBDF1 in cancer cells results in inactivation of EGFR, which leads to cancer cell death and tumor growth inhibition. We are studying the biological activities of RHBDF1, especially its function in the synthesis of EGFR ligands, the signaling pathways involved, and the cause of cell death accompanying the loss of RHBDF1 function. MEMBERS: Fang Tian, PhD Shanghai Institute of Phamarcology Post-Doctoral Research Fellow Patrick Zhou, PhD Peking Union Medical University Post-Doctoral Research Fellow Paulina H. Liang Graduate Student Li Chen, PhD China Medical University Laboratory Manager PUBLICATIONS: Hou, W, Medynski, D, Wu, S, Lin, XL, Li, LY. VEGI-192, a New Isoform of TNFSF15, Specifically Eliminates Tumor Vascular Endothelial Cells and Suppresses Tumor Growth. Clinical Cancer Res. 11:5595-5602, 2005 Tian, F, Grimaldo, S, Mitssugu, F, Cutts, J, Vujanovic, NL, and Li, LY. The Endothelial Cell-Produced Anti-Angiogenic Cytokine Vascular Endothelial Growth Inhibitor (VEGI) Induces Dendritic Cell Maturation. J. Immunol. 179:3742-51, 2007 Yan, ZW, Zou, HF, Tian, F, Grandis, JR, Mixson, AJ, Lu, PY, and Li, LY. Human Rhomboid Family-1 (RHBDF1) Gene-Silencing Causes Apoptosis or Autophagy to Epithelial Cancer Cells and Inhibits Xenograft Tumor Growth. Mol. Cancer Therap. 7:1355-64, 2008 Zou, H, Thomas, SM, Yan, ZW, Grandis, JR, Vogt, A, and Li, LY. Human Rhomboid Family-1 Gene RHBDF1 Participates in GPCR-Mediated Transactivation of EGFR Growth Signals in Head and Neck Squamous Cancer Cells. FASEBJ, Epub ahead of print, 2008