Research Interests and Approaches
Understanding of the fundamental molecular mechanisms for vasculogenesis, arteriogenesis and angiogenesis may lead to improved therapeutic strategies for treatment of vascular diseases. The vascular cells that primarily respond to inflammatory stimuli are the vascular endothelial cells (EC). The goal in my lab is to dissect the signaling pathways in EC involved in vascular development, remodeling and disease progression (see figure 1). We have used biochemical, cell biological and mouse genetic approaches to define the critical molecules mediating vascular development, remodeling and vascular disease progression (see figure 2).
Inflammation-mediated angiogenesis and lymphangiogenesis
Both angiogenesis and lymphangiogenesis are critical for tissue repair. We have identified the TNFR2-Bmx kinase (bone marrow tyrosine kinase in X chromosome)-VEGFR2/3 signaling pathway involved in EC proliferation, migration and tube formation. We are investigating how TNFR2-Bmx mediates angiogenesis, lymphangiogenesis and vascular tissue repair (see figure 3).
Vascular development, endothelial cell progenitor differentiation and vascular malformationIn addition to Bmx, we have identified several intracellular molecules (CCM3 and AIP1) regulating VEGFR2, a critical tyrosine receptor kinase in vascular development, EC progenitor cell differentiation and vascular remodeling. We have generated conditional knockout mice with a deletion of each gene, and these mice will provide useful tools to define the mechanism underlining human vascular diseases such as cerebral cavernous malformations, retinopathy and tumor metastasis.
Stress signaling pathways in EC
We have identified several critical upstream regulators of ASK1 (a member of MAP3K family) and have made several original discoveries in elucidating the mechanisms for ASK1 activation by various stresses (cytokine, oxidative stress, genotoxic stress and ER stress (see figure 4 from a Recent review article in 2009). We are determining how these mediators are specifically activated in response to stress.
Determine the mechanism of tumor progression and metastases
We have identified AIP1, a new member of Ras-GAP family protein (also known as DAB2IP), as a potential tumor suppressor gene. We are employing variety of tumor models to determine the role of AIP1 in tumor growth and metastasis.