Youming Lu, M.D., Ph.D.
Professor of Neurology and Neuroscience
1996-1999: Ph.D., University of Toronto, Canada
2008- Professor, LSU School of Medicine, New Orleans
RESEARCH INTERESTS AND GOAL
I am interested in identifying and characterizing the specific cellular and molecular signaling processes that cause the aberrant changes of synaptic transmission and in applying this knowledge for developing the practical strategies in the treatment of Alzheimer’s diseases and stroke.
Glutamate is the major excitatory transmitter in the mammalian central nervous system (CNS) and plays an essential role in neural development, excitatory synaptic transmission, and plasticity. In case of brain injury such as stroke, however, glutamate accumulates at synapses, resulting in extensive stimulation of its receptors that can eventually be toxic to neurons. Although excess stimulation of glutamate transmission contributes to neuronal death, blocking it totally could be deleterious to animals and humans because targeting glutamate synapses would block the synaptic physiological function as well. My long-term objective is to explore an ideal approach for treatment of some neurological disorders and brain injury by targeting at the specific glutamate “cell death signals” whereby the pathological effects of glutamate transmission is selectively blocked, leaving the physiological action unaffected. To achieve this goal, I am currently investigating the specific cellular and molecular signaling processes that cause the aberrant changes of glutamate transmission with two independent research projects, as summarized in the following working model:
Cell death signals induce the
(A) Under the physiological conditions, excitatory neurotransmitter glutamate releases from the pre-synaptic terminals through synaptic vesicle fusion events, in which Epac, exchange factor that directly activated by cAMP, is involved. Released glutamate binds to its receptors on the post-synaptic sites. One of the principle glutamate receptors is NMDA receptor. Activation of NMDA receptor allows physiological Ca2+ influx and in turn induces gene expression, neuronal growth, synaptic transmission and plasticity. (B) Research in my laboratory has mainly focused on the aberrant changes of synaptic transmission in brain disorders and injury. One of our research projects is targeting to the pre-synaptic terminals, in which Epac mutation deteriorates glutamate release event. We have recently generated the mutant mice with deficiency in expression of Epac genes. We found that genetic deletion of Epac gene declines excitatory synaptic transmission. The second project is focusing on the post-synaptic glutamate receptors. We have discovered that ischemia recruits DAPK1, death-associated protein kinase 1, into the NMDA receptor complex, and induces toxic Ca2+ influx through the receptor channels. We have thus generated the null mutant mice lacking the DAPK1 gene and found that genetic deletion of DAPK1 protects against brain cells death.
Tu, W., Xu, X., Peng, L., Zhong X., Zhang, W., Soundarapandian, M.M., Belal, C., Wang, M., Jia, N., Lew, F., Chan, S.L., Chen, Y., Lu, Y:DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke. Cell (2010) 140:222-234.
ADAR2-dependent RNA editing of AMPA receptor subunit GluR2 in ischemia