Mechanisms of cell death and neuroprotection in cerebral ischemia and Parkinson's disease.
Dr. Chen is the RK Mellon Endowed Professor and Director of the Center of Cerebrovascular Disease Research in the School of Medicine.
Dr. Chen's laboratory is interested in molecular mechanisms of neuronal cell death associated with cerebral ischemia or Parkinson's disease. The work focuses on determining the role of programmed cell death and mitochondrial dysfunction in cellular and animal models. The main theme of this research is that elucidation of the signaling mechanisms underlying the pathologic neurodegenerative processes in the brain may help identify new targets for future therapeutic intervention of the disease. The lab is currently investigating the specific signaling molecules and pathways that trigger mitochondrial apoptosis and downstream caspase-dependent or caspase-independent cell death-execution cascades in neurons.
Another main area of interest of Dr. Chen's laboratory is to elucidate the role of oxidative DNA damage and repair in ischemic brain injury, focusing on the mechanisms associated with the base-excision repair (BER) pathway in neuronal injury. The evolution of oxidative DNA damage, such as single-strand breaks and AP sites, is an early determinant of neuronal cell death or survival in cerebral ischemia. As a highly inducible process, BER is the key mechanism responsible for the repair of various oxidative DNA damage in the brain. This line of research is based on the belief that manipulation of cellular BER activity may markedly impact the vulnerability of neurons to ischemic challenges.
Hu, X., Weng, Z., Chu, C.T., Zhang, L., Cao, G., Gao, Y., Signore, A., Zhu, J., Hastings, T., Greenamyre, J.T. and Chen, J. Peroxiredin-2 protects against 6-hydroxydopamine-induced dopaminergic neurodegeneration via attenuation of the ASK signaling cascade. Journal of Neuroscience (in press).
Stetler, R.A., Gao, Y., Zukin, R.S., Vosler, P.S., Zhang, L., Zhang, F., Cao, G., Bennett, M.V.L., and Chen, J. Apurinic/apyrimidinic endonuclease APE1 is required for PACAP-induced neuroprotection against global cerebral ischemia. Proc Natl Acad Sci U.S.A. 107(7):3204-9, 2010.
Stetler, R.A., Cao, G., Gao, Y., Zhang, F., Wang, S., Weng, Z., Vosler, P., Zhang, L., Signore, A., Graham, S., and Chen, J. Hsp27 protects against ischemic brain injury via attenuation of a novel stress-response cascade upstream of mitochondrial cell death signaling. Journal of Neuroscience 28: 13038-13055, 2008.
Weng, Z., Signore, A., Gao, Y., Hastings, T., Wang, S., Zhang, F., Yin, X.M., and Chen, J. Leptin protects against dopminergic cell death via mitogen-activated protein kinase signaling. J Biol Chem. 2007, 282: 34479-91
Cao, G., Xing, J., Xiao, X., Liou, A.F.K., Yin, X.M., Clark, R.S.B., Graham, S.H. and Chen, J. Critical role of calpain I in mitochondrial release of apoptosis-inducing factor in ischemic neuronal injury. Journal of Neuroscience 27(35): 9278-9293, 2007.
Cao, G., Xiao, M., Xiao, X., Li, J., Pei, W., Yin, X.M., and Chen, J. Molecular Cloning and Characterization of a Novel Apaf-1 Interacting Protein: a potent cell death-suppressor against neuronal apoptosis and ischemic neurodegeneration. Journal of Neuroscience, 24:6189-6201, 2004.