Our research focuses on the mechanisms underlying epileptogenesis, a pathological process by which a brain becomes epileptic, resulting from genetic mutation or neurological insults. Given that current treatments merely suppress but do not cure epilepsy, and that approximately one in every three patients has seizures that are resistant to all available medications, the best way to fight epilepsy is to prevent the disease in the first place by blocking epileptogenesis. We are specifically interested in how the mammalian target of rapamycin (mTOR)/autophagy pathway governs normal brain functions and how dysregulation of this pathway leads to epilepsy. We have two general directions:
1) To investigate how the perturbance of the mTOR/autophagy pathway as a result of either genetic mutation or brain injuries leads to epilepsy.
2) To identify novel genes and signaling molecules that mediate mTOR/autophagy activity.
Together, we believe that better understanding the mTOR/autophagy pathway and its implication in epileptogenesis will aid in developing novel therapeutic strategies to prevent epilepsy.
McMahon J, Huang X, Yang J, Komatsu M, Yue Z, Qian J, Zhu X and Huang Y. Impaired autophagy in neurons following disinhibtion of mTOR and its contribution to epileptogenesis. Journal of Neuroscience. 32(45):15704-14, 2012.
*This work was highlighted in “Cleaning Up Epilepsy and Neurodegeneration: The Role of Autophagy in Epileptogenesis” by Wong M. Epilepsy Curr. 13(4): 177-178, 2013”
Yang J, Dolinger M, Ritaccio G, Mazurkiewicz J, Conti D, Zhu X, and Huang Y. Leucine stimulates insulin secretion via down-regulation of surface expression of adrenergic a2A receptor through the mTOR pathway and its implication in new-onset diabetes in renal transplantation. Journal of Biological Chemistry. 287(29):24795-806, 2012.3.
Huang X, McMahon J, Yang J, Shin D, and Huang Y. Rapamycin down-regulates KCC2 expression and increases seizure susceptibility to convulsants in immature rats. Neuroscience. (219):33-47, 2012.4.
Huang X, McMahon J, Huang Y. Rapamycin attenuates aggressive behavior in a rat model of pilocarpine-induced epilepsy. Neuroscience. (215):90-7, 2012.
Wu J, McCallum SE, Glick SD, Huang Y. Inhibition of the mammalian target of rapamycin pathway by rapamycin blocks cocaine-induced locomotor sensitization. Neuroscience. 172:104-9. 2011.
Huang X, Zhang H, Yang J, Wu J, McMahon J, Lin Y, Cao Z, Gruenthal M, Huang Y. Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. Neurobiol Dis. 40(1):193-9. 2010.
*This work was highlighted in “Rapamycin for treatment of epilepsy: antiseizure, antiepileptogenic, both, or neither?” By Wong M. Epilepsy Curr. (2):66-8, 2011”.
Hou Q, Huang Y, Amato S, Snyder SH, Huganir RL, Man HY. Regulation of AMPA receptor localization in lipid rafts. Mol Cell Neurosci. 38(2):213-23. 2008.
Huang Y, Higginson DS, Hester L, Park MH, Snyder SH. Neuronal growth and survival mediated by eIF5A, a polyamine-modified translation initiation factor. Proceedings of the National Academy of Sciences,104:4194, 2007.
Huang Y, Kang BN, Tian J, Liu Y, Luo HR, Hester L, Snyder SH. The cationic amino acid transporters CAT1 and CAT3 mediate NMDA receptor activation-dependent changes in elaboration of neuronal processes via the mammalian target of rapamycin mTOR pathway. Journal of Neuroscience, 27:449-58, 2007.
Riccio A., Alvania R.S., Bonnie E. Lonze B.E., Taeho Kim T., Huang Y., Dawson T.M., Snyder S.H., and Ginty D.D. A novel neurotrophin signalling pathway controlling CREB activity in neurons. Molecular Cell, 21:283-94, 2006.
Huang Y., and Snyder S.H. Nitrosylation and thiolylation. Encyclopedia of Genomics, Proteomics and Bioinformatics. John Wiley & Sons, Ltd. 2005.
Huang Y., Man H.Y., Sekine-Aizawa Y., Han Y.F., Juluri K., Luo H., Cheah J., Lowenstein C., Huganir R. L., and Snyder S.H. S-nitrosylation of N-ethylmaleimide sensitive factor (NSF) mediates surface expression of AMPA receptors. Neuron 46(4):533-40, 2005.
Myers S.J., Huang Y., Genetta T., and Dingledine R. Inhibition of glutamate receptor 2 translation by a polymorphic repeat sequence in the 5'-untranslated leaders. Journal of Neuroscience 24(14):3489-99, 2004.
Luo H.R., Hattori H., Hossain M.A., Hester L., Huang Y., Lee-Kwon W., Donowitz M., Nagata E., and Snyder S.H. Akt as a mediator of cell death. Proc Natl Acad Sci U S A. 100(20):11712-7, 2003.
Luo H.R., Huang Y.E., Chen J.C., Saiardi A., Iijima M., Ye K., Huang Y., Nagata E., Devreotes P., and Snyder S.H. Inositol pyrophosphates mediate chemotaxis in Dictyostelium via pleckstrin homology domain-PtdIns(3,4,5)P3 interactions. Cell 114(5):559-72, 2003.
Huang Y., Doherty J.J., and Dingledine R. Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. Journal of Neuroscience 22(19):8422-8, 2002.
Roopra A., Huang Y., and Dingledine R. Neurological disease: listening to gene silencers. Molecular Intervention 1(4):219-28, 2001.
Huang Y., Myers S.J., and Dingledine R. Transcriptional repression by REST involves recruitment of histone deacetylase to neuron-selective promoters. Nature Neuroscience 10(2): 867-872, 1999.
Myers S.J., Peters J., Huang Y., Comer M.B., Bathel F., and Dingledine R. Transcriptional regulation of the GluR2 gene: neural-specific expression, multiple promoters, and regulatory elements. The Journal of Neuroscience 18(7): 6723-6739, 1998.