Research
Understanding of the fundamental molecular mechanisms for vasculogenesis, arteriogenesis and angiogenesis may lead to improved therapeutic strategies for treatment of both vascular diseases and cancer. 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 atherosclerosis, vascular remodeling and tumor progression (Fig.1). We have used both biochemistry and mouse genetic approaches to define the critical molecules mediating inflammatory response and their roles in vascular disease progression (Fig.2).
Major Ongoing Projects: Our major research contributions and ongoing projects are as follows:
1. Inflammation-mediated angiogenesis and lymphangiogenesis (Fig.3). Both angiogenesis and lymphangiogenesis are criticl for tumor growth and metastasis. We were the first to identify a TNFR2-Bmx kinase (bone marrow tyrosine kinase in X chromosome) pathway, and further provided the first in vitro and the first in vivo evidence to demonstrate its critical role in angiogenesis. We are currently investigating their roles in lymphangiogenesis and tumor metastasis.
2. 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 TNF via AIP1, oxidative stress via PKD, genotoxic stress via HIPK1 and ER stress via IRE1 (see Fig.4 from a Recent review article in 2008). We are determining how these mediators are specifically activated in response to stress.
3). 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.
4. Vascular development and endothelial stem
cell. Recently we have generated several knockout mice with
deficiencies of key molecules involved redox and apoptotic signaling
such as mitochondrial thioredoxin and SUMO proteases SENP1. Genetic
deficiencies of these molecules cause defects in vascular development
and remodeling, in part, due to defects in generation of vascular stem/progenitor
cells. We will further define the role of these molecules in self-renewal
and differentiation of stem/progenitor cells. These mice will provide
useful tools to define the mechanism underlining human vascular diseases
such as cerebral cavernous malformations, Alzheimer’s disease and tumor
metastasis.
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People
Current Lab members:
Haifeng Zhang, Ph.D; Yun He, M.D., Ph.D;
Shengchuan Dai, M.D., Ph.D
Dianhong Luo, Ph.D; Luyang Yu, Ph.D
Dennis Jones, Ph.D student
Ting Wan, M.D, Joint Ph.D student; Zhe Xu, M.D., Joint Ph.D student
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Publications
Recent Publications:
He, Y, Luo, Y, Tang, S., Rajantie, I, Salven, P, Heil, M, Zhang, R, Luo, D, Li, X., Chi, H, Yu, J, Carmeliet, P., Schaper, W, Sinusas, A.J, Sessa, W.C, Alitalo, K, and Min, W.* (2006) Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis. J. Clin. Invest., 116 (9), 2344-55.
Luo, D., Luo, Y., He, Y., Zhang, H., Zhang, R., Li, X., Dobrucki, W.L., Sinusas, A.J., Sessa, W.C., and Min, W*. (2006) Differential functions of TNFR1 and TNFR2 signaling in ischemia-mediated arteriogenesis and angiogenesis. Am J. Pathol. 169 (5), 1886-98.
Zhang, H., Luo, Y., Zhang, W., He, H., Zhang, R., Huang, Y., Bernatchez, P., Giordano, F.J., Shadel, G., Sessa, W.C., and Min, W*. (2007) Endothelial-specific expression of mitochondrial thioredoxin improves endothelial cell function and reduces atherosclerosis. Am J. Pathol. 170 (3), 1108-20. (see Editorial Comment on page 805).
Zhang, H., Zhang, H., Lin, Y., Li, J., Pober, J.S., and Min, W*. (2007) RIP1-mediated AIP1 phosphorylation at a 14-3-3-binding site is critical for TNF-induced ASK1-JNK/p38 activation. . J. Biol. Chem. 282(20), 14788-96.
Hsieh, J.T., Karam, J.A., Min, W. (2007) Genetic and biologic evidence that implicates a gene in aggressive prostate cancer. J Natl Cancer Inst. 99(24):1823-4.
Li, X., Luo, Yu, L., Yan, L., Luo, D., Zhang, H., He, Y., Kim, Y.O., Kim, Y., Tang, S. and Min, W*. (2008). SENP1 mediates TNF-induced desumoylation and cytoplasmic translocation of HIPK1 to enhance ASK1-dependent apoptosis. Cell Death Differ.15 (4): 739-50.
Luo, D., He, Y., Zhang, H., Yu, L., Chen, H., Tang, S., Urano, F., and Min, W* (2008) AIP1 is critical in transducing IRE1-mediated endoplasmic reticulum stress response. J. Biol. Chem. Feb 15; [Epub ahead of print].
Min, W*., Lin, Y., Tang, S., Yu, L., Zhang, H., Wan, T., Luhn, T., Fu, H. and Chen, H. (2008). AIP1 recruits PP2A to ASK1 in TNF-induced ASK1-JNK activation. Cir. Res. 102 (7): 840-8.
Pober, JS, Min, W., and Bradley, JR (2008) Endothelial Dysfunction, Injury and Death. Ann Rev Pathology: Mechanism of Disease. In press.
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