Research & Publications
Understanding of the fundamental molecular mechanisms for inflammation may lead to improved therapeutic strategies for treatment of vascular diseases such as atherosclerosis. The vascular cells that primarily respond to inflammatory stimuli are the vascular endothelial cells (EC). The goal in my lab is to dissect the inflammatory signaling pathways in EC involved in vasculature. For over 15 years, my laboratory has been funded through 8 NIH, 3 AHA grants and 2 industry Research Agreements to define the critical molecules mediating inflammatory responses, and their roles in progression of vascular diseases such as atherosclerosis, graft transplant rejection and tumor metastasis. We have been the leader in the field of inflammation/stress signaling.
Since 2008, my lab has expanded our research to vascular development and remodeling. The goal in my lab is to dissect the signaling pathways, establish mouse models and define the fundamental mechanisms involved in vascular development, remodeling and repair related to human diseases such as vascular malformation, ischemia and stroke. In the past 4 years, my lab has extensively employed biochemical, cell biological and mouse genetic approaches to define the critical molecules mediating vascular development, remodeling and repair. These new projects are currently funded by 2 NIH (as PI) and 2 AHA (as a mentor) grants. These projects fit very well to the overall research mission in the Department of Pathology and the Program of Vascular Biology & Therapeutics (VBT).
Extensive Research Description
Research Interests and Approaches: Understanding of the fundamental molecular mechanisms for vasculogenesis, arteriogenesis, angiogenesis and lymphangiogenesis 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 (Fig.1). We have used biochemical, cell biological and mouse genetic approaches to define the critical molecules mediating vascular development, remodeling and vascular disease progression (Fig.2).
1. Inflammation-mediated angiogenesis and lymphangiogenesis (Fig.3). 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.
2. Vascular development, endothelial cell progenitors and vascular malformation. In addition to Bmx, we have identified several intracellular molecules (AIP1, CCM3 and Epsin) 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.
3. 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 Fig.4 from a Recent review article in 2009). We are determining how these mediators are specifically activated in response to stress.
4. 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.
Heart Diseases; Vascular Diseases; Cardiovascular Abnormalities
Public Health Interests
Cancer; Cardiovascular Diseases