鲁白

Bai Lu, Ph.D.



Unit on Synapse Development & Plasticity

NICHD, NIH

Building 49, Rm. 6A-80

49 Convent Dr., MSC4480

Bethesda, MD 20892-4480



(301) 435-2970 (p)

(301) 496-1777 (f)

bailu@mail.nih.gov



Dr. Lu received his B.Sc. degree from East China Normal University and his Ph.D. from Cornell University Medical College, where he studied regulation of neurotrophin gene expression in the brain with Ira Black. He did his postdoctoral work at Rockefeller University with Paul Greengard and Mu-ming Poo on molecular mechanism of synaptic transmission and development, using the Xenopus neuromuscular synapses as a model system. In 1993, he became a faculty member at Roche Institute of Molecular Biology, where he began studying the role of neurotrophins in synapse development and plasticity. He joined NICHD as an Investigator in 1996. His laboratory investigates the mechanisms underlying neurotrophic regulation of synapses, and their functional significance.

Recent (2002) Publications



1. C. Wang, F. Yang, X. He, , H.-S. Je, J.-Z. Zhou, K. Eckermann, D. Kawamura, L. Shen, and B. Lu. (2002) Regulation of Neuromuscular Synapse Development by Glial Cell Line-derived Neurotropic Factor and Neurturin. J. Biol. Chem. 277(12), 10614-10625. (pdf).



2. L. Shen, J. G. Pichel, T. Mayeli, H. Sariola, B. Lu and H. Westphal (2001) GDNF haploinsufficiency causes Hirschspung-like intestinal obstruction and early onset lethality in mice. Am. J. Human Genetics In Press. (pdf)



3. Z. G. Luo, Q. Wang, J. Z. Zhou, J. B. Wang, M. Y. Liu, X. He, A. Wynshaw-Boris, W. C. Xiong, B. Lu, and L. Mei (2002) Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Neuron 35, 489-505.(pdf)



4. D. E. Cabin, K. Shimazu, D. Murphy, N. Cole, W. A. Gottschalk, K. McIlwain, B. Orrison, A. Chen, L. Garret, C. Ellis, R. Paylor, B. Lu (co-corresponding author) and R. L. Nussbaum (2002) Synaptic vesicle depletion in mice lacking alpha-synuclein. J. Neurosci. 22, 8797-8807. (pdf)



5. R. Hashimoto, N. Takei, K. Shimazu, L. Christ, B. Lu, and D.-M. Chuang. (2002) Expression of brain-derived neurotrophic factor and activation of TrkB are necessary for lithium protection against glutamate excitotoxicity in rodent cortical neurons. Neuropharmacology. In press.



6. M. F. Egan, M. Kojima, J. H. Callicott, T. E. Goldberg, B. S. Kolachana, E. Zaistev, A. Bertolino, B. Gold, D. Goldman, M. Dean, B. Lu, (co-corresponding author) and D. R. Weinberger. (2003) A single nucleotide polymorphism in BDNF gene affects regulated secretion of BDNF and human memory and hippocampal function. Cell In press.



7. L. Ma, Y. -Z. Huang, J. Valtschanoff, L. Feng, B. Lu, W. Xiong, R. Weinberg, L. Mei. (2003) Ligand-dependent recruitment of the neuregulin signaling complex into neuronal lipid rafts. J. Neurosci. In press

Research Papers



1. H. G. Kim, T. Wang, P. Olafsson, and B. Lu. (1994) Neurotrophin-3 potentiates neuronal excitability and inhibits g-aminobutyratergic synaptic transmission in cortical neurons. Proc. Natl. Acad. Sci. USA 91, 12341-12345.



2. T. Wang, Z. Xie, and B. Lu, (1995) Nitric oxide mediates activity-dependent synaptic suppression at developing neuromuscular synapses. Nature 374, 262-266.



3. P. Olafsson, T. Wang, and B. Lu. (1995) Molecular cloning and functional characterization of Xenopus Ca2+- binding protein frequenin. Proc. Natl. Acad. Sci. USA 92, 8001-8005.



4. T. Wang, K. Xie, and B. Lu. (1995) Neurotrophins promote maturation of developing neuromuscular synapses. J. Neurosci. 15, 4796-4805.



5. A. Figurov, L. Pozzo-Miller, T. Wang, P. Olafsson, and B. Lu. (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381, 706-709.



6. P. Olafsson, H. D. Soares, K-H. Herzog, T. Wang, J. I. Morgan, and B. Lu. (1997) The Ca2+ binding protein, frequenin is a nervous system-specific protein in mouse preferentially localized in neurites. Mol. Brain Res. 44, 73-82. (pdf)



7. K. Xie, T. Wang, P. Olafsson, K. Mizuno, and B. Lu. (1997) Activity-dependent expression of NT-3 in muscle cells in culture: Implications in the development of neuromuscular junctions. J. Neurosci. 17, 2947-2958. (pdf)



8. C. -Y. Wang, J. Ni, H. Jiang, T. -A. Hsu, M. Dugich-Djordjevic, L. Feng, M. Zhang, L. Mei, R. Gentz, and B. Lu. (1998) Cloning and characterization of glial cell line-derived neurotrophic factor receptor beta: A novel receptor for members of glial cell line-derived neurotrophic factor family of neurotrophic factors. Neurosci. 83, 7-14. (pdf unavailable at this time)



9. W. A. Gottschalk, L. Pozzo-Miller, A. Figurov, and B. Lu. (1998) Presynaptic modulation of synaptic transmission and plasticity by brain-derived neurotrophic factor in the developing hippocampus. J. Neurosci. 18, 6830-6839. (pdf)



10. L. Pozzo-Miller, W. A. Gottschalk, L. Zhang, K. McDermott, J. Du, R. Gopalakrishnan, C. Oho, Z. Sheng, and B. Lu. (1999) Impairments in high frequency transmission, synaptic vesicle docking and synaptic protein distribution in the hippocampus of BDNF knockout mice. J. Neurosci. 19, 4972-4983. (pdf)



11. L. Feng, C. Wang, H. Jiang, C. Oho, M. Dugich-Djordjevic, L. Mei, and B. Lu. (1999) Differential signaling of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor in cultured ventral mesencephalic neurons. Neuroscience. 93, 265-273. (pdf)



12. L. Feng, C. Wang, H. Jiang, C. Oho, K. Mizuno, M. Dugich-Djordjevic, and B. Lu. (1999) Differential effects of GDNF and BDNF on cultured ventral mesencephalic neurons. Mol. Brain Res. 66, 62-70. (pdf)



13. W. A. Gottschalk, H. Jiang, N. Tartaglia, C. Oho, L. Feng, A. Figurov, and B. Lu. (1999) Signaling mechanisms mediating BDNF modulation of synaptic plasticity in the hippocampus. Learning and Memory. 6, 243-256. (pdf)



14. X. He, F. Yang, Z. Xie, and B. Lu. (2000) Intracellular Ca2+ and Ca2+/calmodulin dependent kinase II mediate acute potentiation of neurotransmitter release by neurotrophin-3. J. Cell Biol. 149, 783-791. (pdf)



15. B. Xu, W. Gottschalk, A. Chow, R. I. Wilson, E. Schnell, K. Zang, D. Wang, R. A. Nicoll, B. Lu, L. F. Reichardt. (2000) The role of BDNF receptors in the mature hippocampus: Modulation of long-term potentiation through a presynaptic mechanisms involving TrkB. J. Neuroscience 20, 6888-6897. (pdf)



16. J. Du, L. Feng, F. Yang, and B. Lu. (2000) Activity and Ca2+-dependent modulation of surface expression of BDNF receptors in hippocampal neurons. J Cell Biol. 150, 1423-1433. (pdf)



17. F. Yang, X. He, L. Feng, K. Mizuno, X. Liu, J. Russell, W. Xiong, and B. Lu. (2001) Phosphoinositide-3 kinase and IP3 are both necessary and sufficient to mediate NT3-induced synaptic potentiation. Nature Neurosci. 4, 19-28. (pdf)



18. N. Tartaglia, J. Du, W. J. Tyler, E Neale, L Pozzo-Miller and B. Lu. (2001) Protein synthesis dependent and independent regulation of hippocampal synapses by brain-derived neurotrophic factor. J. Biol. Chem. 276, 37585-37593. (pdf)



19. C. Wang, F. Yang, X. He, A. Chow, J. Du, J. Russell, and B. Lu. (2001) Ca2+-binding protein frequenin mediates GDNF-induced synaptic facilitation by potentiation Ca2+ channels and transmitter release. Neuron 32, 99-112. (pdf)



20. F. Yang, L. Feng, F. Zheng, S. W. Johnson, J. Du, L. Shen, C. -P. Wu, and B. Lu. (2001) GDNF acutely modulates neuronal excitability and A-type potassium channels in midbrain dopaminergic neurons. Nature Neurosci. Published online 10/2/01. (pdf)



21. C. Wang, F. Yang, X. He, , H.-S. Je, J.-Z. Zhou, K. Eckermann, D. Kawamura, L. Shen, and B. Lu. (2002) Regulation of Neuromuscular Synapse Development by Glial Cell Line-derived Neurotropic Factor and Neurturin. J. Biol. Chem. 277(12), 10614-10625. (pdf).



22. L. Shen, J. G. Pichel, T. Mayeli, H. Sariola, B. Lu and H. Westphal (2001) GDNF haploinsufficiency causes Hirschspung-like intestinal obstruction and early onset lethality in mice. Am. J. Human Genetics In Press. (pdf)



23. Z. G. Luo, Q. Wang, J. Z. Zhou, J. B. Wang, M. Y. Liu, X. He, A. Wynshaw-Boris, W. C. Xiong, B. Lu, and L. Mei (2002) Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Neuron 35, 489-505.(pdf)



24. D. E. Cabin, K. Shimazu, D. Murphy, N. Cole, W. A. Gottschalk, K. McIlwain, B. Orrison, A. Chen, L. Garret, C. Ellis, R. Paylor, B. Lu (co-corresponding author) and R. L. Nussbaum (2002) Synaptic vesicle depletion in mice lacking alpha-synuclein. J. Neurosci. 22, 8797-8807. (pdf)



25. R. Hashimoto, N. Takei, K. Shimazu, L. Christ, B. Lu, and D.-M. Chuang. (2002) Expression of brain-derived neurotrophic factor and activation of TrkB are necessary for lithium protection against glutamate excitotoxicity in rodent cortical neurons. Neuropharmacology. In press.



26. M. F. Egan, M. Kojima, J. H. Callicott, T. E. Goldberg, B. S. Kolachana, E. Zaistev, A. Bertolino, B. Gold, D. Goldman, M. Dean, B. Lu, (co-corresponding author) and D. R. Weinberger. (2003) A single nucleotide polymorphism in BDNF gene affects regulated secretion of BDNF and human memory and hippocampal function. Cell In press.



27. L. Ma, Y. -Z. Huang, J. Valtschanoff, L. Feng, B. Lu, W. Xiong, R. Weinberg, L. Mei. (2003) Ligand-dependent recruitment of the neuregulin signaling complex into neuronal lipid rafts. J. Neurosci. In press


 



Reviews and Book Chapters (back to top)



1. B. Lu, M. Yokoyama, C. F. Dreyfus and I. B. Black. (1991) Nerve growth factor gene expression in actively growing brain glia. In: F. Hefti, Ph. Brachet, B. Will and Y. Christen (Eds) Growth factors and Alzheimer’s disease. Springer-Verlag. Berlin. p61.



2. B. Lu and W. -m. Fu. (1995) Regulation of postsynaptic responses by calcitonin gene-related peptide and ATP at developing neuromuscular junctions. Can. J. Phyiol. & Pharmacol. 73, 1050-1056.



3. B. Lu and W. Gao (1997) The use of neurotrophic factors as novel therapeutic agents for diseases in the nervous system. In "Guide to research and Development of New Drugs" Ed. H. Zhou, R. W. Zhang Health and Science Press. Beijing, China. 1997.PP 315-323.



4. L. Shen, A. Figurov, and B. Lu (1997) Recent progress in studies of neurotrophic factors and their clinical implications. J. Mol. Medicine 75, 637-644. (pdf)



5. B. Lu, and A. Figurov. (1997) Role of neurotrophins in synapse development and plasticity. Reviews in The Neuroscience. 8, 1-12.



6. W. Gao, M. M. Dugich-Djordjevic, R. J. Weil and B. Lu. (1997) Therapeutical usage of neurotrophic factors: patent analysis. Expert Opinion on Therapeutic Patents.

7, 325-338.



7. B. Lu, and A. Chow (1999) Neurotrophins and hippocampal synaptic plasticity. J. Neurosci. Res. 58, 76-87. (pdf)



8. B. Lu, and W. Gottschalk (2000) Regulation of in hippocampal synaptic plasticity by neurotrophins. Progress in Brain Res. 128, 231-241.



9. B. Lu, (2000) Neurotrophic regulation of synapse development and plasticity by. Progress in Natural Sciences. 43, 1-5.


 

http://dir2.nichd.nih.gov/nichd/usdp/research.htm



Current Projects :



Mechanisms by which BDNF regulates long-term potentiation (LTP)

We have previously demonstrated that BDNF facilitates LTP by enhancing ability of hippocampal synapses to follow high frequency, LTP-inducing tetanic stimulation (Nature, ’96; J. Neurosci., ’98). This is achieved, at least in part, by promoting synaptic vesicle docking, possibly through regulation of the levels of the synaptic proteins synaptophysin and synaptobrevin in the presynaptic terminals (J. Neurosci., ’99). Using a conditional knockout mouse line in which the BDNF receptor TrkB has been selectively deleted in postsynaptic neurons, we demonstrated this year that at CA1 hippocampal synapses, BDNF acts exclusively on presynaptic neurons but not on postsynaptic neurons, an issue under considerable debate (J. Neurosci. ’00). We have also extended our work to long-term, cAMP and protein synthesis dependent regulation of hippocampal synapses by BDNF (J. Biological Chemistry, ’01). We are currently investigating the role of BDNF in the long-lasting LTP, using transgenic and knockout approaches.



Signal transduction mechanisms for acute effects of neurotrophins

In the hippocampus, BDNF modulation of synaptic plasticity is mediated by signaling pathways involving MAP kinase and Phosphoinositide-3 kinase (PI3K), but not Phospholipase C-gamma (Learning and Memory, 1999). We demonstrated that acute modulation of NT3 on transmitter release at the NMJ uses an unusual mechanism which involves calcium release from intracellular stores through inositol 1, 4, 5-trisphosphate (IP3) and/or ryanodine receptors, leading to an activation of calcium/calmodulin kinase II (CaMKII) (J. Cell Biol., ’00). Further, we demonstrated using photo-uncaging that simultaneous activation of PI3K and IP3 receptors is not only necessary but also sufficient to mediate the effect of NT3 (Nature Neurosci., ’01). We are continuing to investigate the key signaling mechanisms underlying acute and long-term neurotrophic regulation, as well as mechanisms by which acute effects can be converted into long-term modulation.



Activity-dependent modulation of neurotrophin receptors

To understand how synapse specific neurotrophic regulation is achieved, we have examined the role of neuronal/synaptic activity in the trafficking of the neurotrophin receptors TrkB. We revealed an activity-dependent modulation of the insertion of TrkB into the plasma membrane of cultured hippocampal neurons. This effect requires Ca2+ influx through NMDA-type glutamate receptors and Ca2+ channels, and involves CaMKII (J. Cell Biol., ’00). We are actively pursuing this line of research, with particular emphasis on activity-dependent regulation of TrkB internalization, and intracellular signaling. These studies may not only provide insights into the mechanistic link between activity-dependent and neurotrophic modulation of synaptic efficacy, but also have general implications in the cell biology of growth factor signaling.



Role of GDNF family proteins on neuronal and synaptic functions

We have preciously cloned a new GDNF receptor (Neuroscience, ’98) and demonstrated that differential signaling of GDNF and BDNF may mediate differential functions by these two factors in the midbrain dopaminergic neurons (Neuroscience, ’99; Mol. Brain Res., ’99). Recently, we discovered an unexpected, acute effect of GDNF on A-type potassium channels, leading to a potentiation of neuronal excitability, in the dopaminergic neurons in culture as well as in adult brain slices (Nature Neurosci., ’01). Further, we show that GDNF regulates the K+ channels through a mechanism that involves activation of MAP kinase. We have also used the Xenopus NMJ as a model system to study the synaptic effects of GDNF. We found that long-term application of GDNF to the NMJ facilitates synaptic transmission by enhancing release probability. This effect is mediated by up-regulation of the calcium binding protein frequenin, which interacts with the N-type calcium channels at the nerve terminals (Neuron, ’01). We are further characterizing the pre- and postsynaptic effects of the GDNF family of proteins on neuromuscular development.