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Section on Signal Transduction
Laboratory of Molecular Biology
Gonda Department of Cell and Molecular
Biology

For information, please call:
Jian-Dong Li, M.D., Ph.D. 

(213) 273-8083
(213) 273-8088 Fax
jdli@hei.org
Mission Statement

Our mission is to elucidate the signal transduction mechanisms involved in bacterial pathogenesis of Nontypeable Haemophilus influenzae and Streptococcus pneumoniae infections including otitis media (OM) and chronic obstructive pulmonary diseases (COPD). Understanding these signaling mechanisms will open up novel therapeutic targets for prevention and treatment of otitis media and COPD.

Research

  1. Signaling Mechanisms Involved in Bacteria-induced Up-regulation of Mucin

    Mucin overproduction is a major cause of conductive hearing loss in otitis media and airway obstruction in COPD. The molecular mechanisms by which mucin is up-regulated are unknown. The goal of this project is to investigate the signaling mechanisms underlying bacteria-induced mucin transcription.

  2. Regulation of Toll-like Receptor in Bacteria Infections

    Toll-like receptors play a crucial role in host immune and defense response against invading bacterial pathogens. Although the expression of TLR2 is low in the surface epithelial cells, the first line of host defense against bacteria, it can be greatly up-regulated by bacteria during bacteria infections. This project aims to fully understand the signaling pathways involved in TLR2 regulation in the pathogenesis of bacterial infectious diseases.

  3. Combinatorial Regulation of Inflammation in Bacteria Infections

Inflammation is a hallmark of respiratory bacteria infections including otitis media and COPD. In view of the current studies on regulation of NF-kB, the key regulator of inflammation, most studies have focused on investigating NF-kB regulation by a single inducer at one time. Given the fact that, in the in vivo situation, multiple pathogenic inducers are existing simultaneously, it remains unclear whether multiple factors simultaneously regulate NF-kB in a combinatorial manner. The goal of this work is to investigate the signaling networks involved in the combinatorial regulation of inflammation in bacteria infections.

Research Staff

  • Jian-Dong Li, M.D., Ph.D., Section Chief

  • Ran Chen, Ph.D., Post-doctoral Scientist

  • Un-Hwan Ha, Ph.D., Post-doctoral Scientist

  • Akira Imasato, Graduate Student

  • Jae Hyang Lim, Ph.D., DVM, Post-doctoral Scientist

  • Hirofumi Jono, Ph.D., Post-doctoral Scientist

  • Soo-Mi Kweon, Ph.D., Post-doctoral Scientist

  • Fumi Mikami, Graduate Student

  • Davida Rixter, Medical Student

  • Akihiro Sakai, Ph.D., Post-doctoral Scientist

  • Haidong Xu, M.D., Advanced Research Associate

  • Hiroki Yoshida, Graduate Student

 

Signaling networks involved in the pathogenesis of NTHi infections. (Click here for larger view.)


From left: A. Imasato, A. Sakai, T. Watanabe, H. Xu, B. Wang, H. Jono, D. Rixter and J. Li

 

 

 

 

 

 

 

 

 

 




Selected Publications

  1. Jono, H., Xu, H., Kai, H., Lim, D.J., Kim, Y.S., Feng, X.H. and Li, J.D. TGF-ß-Smad Signaling Pathway Negatively Regulates Nontypeable Haemophilus influenzae-induced MUC5AC Mucin Transcription via MAPK Phosphatase-1-dependent Inhibition of p38 MAPK. J. Biol. Chem. (In Press), 2003.
  2. Li, J.D. Exploitation of host epithelial signaling networks by respiratory bacterial pathogens. J. Pharmacol. Sci. 91:1-7, 2003.
  3. Imasato, A., Desbois-Mouthon, C., Han, J., Kai, H., Cato, A.C., Akira, S., Li, J.D. Inhibition of p38 MAPK by glucocorticoids via induction of MAP kinase phosphatase-1 enhance nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2. J. Biol. Chem. 277:47444-47450, 2002.
  4. Jono, H., Shuto, T., Xu, H., Kai, H., Lim, D.J., Gum, J.R., Kim, Y.S., Yamaoka, S, Feng, X.H. and Li, J.D. Transforming Growth Factor-ß-Smad Signaling Pathway Cooperates with NF-B to Mediate Nontypeable Haemophilus influenzae-induced MUC2 Mucin Transcription. J. Biol. Chem. 277:45547-45557, 2002.
  5. Shuto, T., Imasato, I., Jono, H., Xu, H., Watanabe, T., Kai, H., Andalibi, A., Linthicum, F., Guan, Y.L., Han, J., Cato, A.C., Akira, S., Lim, D.J. and Li, J.D. Glucocorticoids synergistically enhance Nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via a negative cross-talk with p38 MAP kinase. J. Biol. Chem. 277:17263-17270, 2002.
  6. Wang, B., Lim, D.J., Han, J., Kim, Y.S., Basbaum, C.B. and Li, J.D. Novel Cytoplasmic Proteins of Nontypeable Haemophilus influenzae Up-regulate Human MUC5AC Mucin Transcription via a Positive p38 MAP Kinase Pathway and a Negative PI 3-Kinase-Akt Pathway. J. Biol. Chem. 277:949-957, 2002.
  7. Lee, H.W., Ahn, D.H., Crawley, S.C., Li, J.D., Gum, J.R., Basbaum, C.B., Fan, N.Q., Symkowski, D.E., Han, S.Y., Lee, B.H., Sleisenger, M.H. and Kim, Y.S. Phorbol 12-myristate 13-acetate up-regulates the transcription of MUC2 intestinal mucin via Ras, ERK and NF-kB. J. Biol. Chem. 2002 Jun 20 [epub ahead of print].
  8. Bakaletz, L.O., Juhn, S.K., Jung, T.T. and Li, J.D. Recent advances in otitis media. 5. Molecular biology and biochemistry. Ann. Otol. Rhinol. Laryngol. 188 (Suppl):52-61, 2002.
  9. Moon, S.K., Lee, H.Y., Li, J.D., Nagura, M., Kang, S.H., Chun, Y.M., Linthicum, F.H., Ganz, T., Andalibi, A. and Lim, D.J. Activation of a Src-dependent Raf-MEK1/2-ERK signaling pathway is required for IL-1a-induced upregulation of b-defensin 2 in human middle ear epithelial cells. Biochim. Biophys. Acta. 1590:41-51, 2002.
  10. Jono, H., Xu, H., Kai, H., Gum, J., Kim, Y.S., Feng, X.H. and Li, J.D. Direct activation of TGF-b-Smad signaling by nontypeable Haemophilus influenzae mediates host defensive responses (J. Biol. Chem. In revision, 2002)
  11. Shuto, T., Xu H., Wang, B, Han, J., Kai, H., Gu, X.X., Murphy, T., Lim, D.J. and Li, J.D. Activation of NF-kB by Nontypeable Haemophilus influenzae is mediated by Toll-like Receptor-2-TAK1-dependent NIK-IKKa/b-IkBa and MKK3/6-p38 MAP kinase signaling pathways. Proc. Natl. Acad. Sci. USA, 98:8774-8779, 2001.
  12. Feng, W., Webb, P., Nguyen, P, Liu, X., Li, J.D., Karin, M. & Kushner, P.J. Potentiation of estrogen receptor activation function 1 (AF-1) by Src/JNK through a serine 118-independent pathway. Mol Endocrinol. 15, 32-45, 2001.
  13. Lim, D.J., Chun, Y. M., Lee, H.Y., Moon, S. K., Li, J.D. & Andalibi, A. Cell biology of tubotympanum in relation to pathogenesis of otitis media. Vaccine 19(S1), S17-25, 2000.
  14. Longphre, M., Li, D., Li, J.D., Matovinovic, E., Gallup, M., Samet, J.M. and Basbaum, C. Lung mucin production is stimulated by the air pollutant residual oil fly ash. Toxicol. Appl. Pharmacol. 162:86-92, 2000.
  15. Li, J.D., Feng, W.J., Gallup, M.G., Gum, J., Kim, Y. & Basbaum, C. Activation of NF-kB via a Src-dependent MAPK-pp90rsk pathway is required for P. aeruginosa-induced mucin overproduction in epithelial cells. Proc. Natl. Acad. Sci. USA, 95:5718-5723, 1998.
  16. Basbaum, C., Li, J.D. Up-regulation of airway mucin by Pseudomonas aeruginosa in the pathogenesis of cystic fibrosis. In: Baum/Priel et al., ed. Cilia, Mucus and Mucociliary Interactions, New York, NY: Dekker Press, 1998.
  17. Lim, M., Martinez, T., Jablons, D., Cameron, R., Guo, H., Toole, B., Li, J.D & Basbaum, C. Tumor-derived EMPRIN stimulates collagenase transcription through MAP kinase p38. EEBS Lett, 441:88-92, 1998.
  18. Dohrman, A., Miyata, S., Gallup, M., Li, J.D., Chapelin, C., Nadel J. and Basbaum, C. Transcriptional regulation of mucin MUC2 and MUC5AC genes by bacteria. BBA , 1406:251-9, 1998.
  19. Li, J.D., Dohrman, A., Gallup, M., Miyata, S., Gum, J., Kim, Y., Nadel, J., Prince, A. and Basbaum, C. Transcriptional activation of MUC2 mucin gene by P. aeruginosa in the pathogenesis of cystic fibrosis. Proc. Natl. Acad. Sci. USA, 94:967-972, 1997.
  20. Nagomi, H., Ohmori, H., Li, J.D., Gallup, M., Gum, J., Kim, Y. & Basbaum, C. Sp1 protein contributes to airway-specific rat MUC-2 mucin gene transcription. Gene, 198,:191-201, 1997.
  21. Basbaum, C., Li, J.D. and M. Lim. Airway gland growth and differentiation. In: McDonald, J.A., ed. Lung Growth and Development, New York, NY: Dekker Press, 163-180, 1997.
  22. Kai, H., Takeuchi, K., Omori, H., Li, J.D., Gallup, M. & Basbaum, C. Transcriptional regulation of the lysozyme gene in airway gland serous cells. J. Cell. Biochem. 61:350-62, 1996.  
  23. Cao, W., Govardovskii, V., Li, J.D. & Steinberg, R.,H. Systemic hypoxia dehydrates the space surrounding photoreceptors in the cat retina. Invest. Ophthalmol. & Vis. Sci. 37:586-596, 1996.
  24. Li, J.D., Govardovskii, V. & Steinberg, R.H. Light-dependent hydration of the space surrounding photoreceptors in the cat retina in vivo. J. Vis. Neurosci. 11:743-752. 1994.
  25. Gallemore, R.P., Li, J.D., Govardovskii, V. & Steinberg, R.H. Calcium gradients and light-evoked calcium changes outside rods in the intact cat retina in vivo. J. Vis. Neurosci. 11:753-761, 1994.
  26. Li, J.D., Gellemore, R.P., Dmitriev, A.V. & Steinberg, R.H. Light-dependent hydration of the space surrounding photoreceptors in the chick retina. Invest. Ophthalmol. & Vis. Sci. 35:2700-2711, 1994.
  27. Govardovskii, V., Li, J.D., Dmitriev, A.V. & Steinberg, R.H. Mathematical model of TMA diffusion and prediction of the light-dependent subretinal hydration in chick retina. Invest. Ophthalmol. & Vis. Sci. 35:2712-2724. 1994.
  28. Tian, W.L., Li, J.D. & Li, H.S. Electrophysiological characteristics in acute methanol toxication. Chinese J Ophthalmic Research 9:32-35, 1991.
  29. Yang, X.L., Fan, T.X. & Li, J.D. Dark adaptation of horizontal cells in the teleomost fish retina. Science in China 34:611-619. 1991.
  30. Yang, X.L., Fan, T.X. & Li, J.D. Electroretinographic b-wave merely reflects the activity of the rod system in the dark-adapted carp retina. Vision Research 30:993-999, 1990.95:5718-5723.

 

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