About the Director
Dr. Jian-Dong Li is the founding director of the Institute for Biomedical Sciences at Georgia State University. He is responsible for leading the joint effort to establish a leading multidisciplinary research and degree-granting institute at Georgia State. The Institute for Biomedical Sciences is dedicated to advancing fundamental and innovative biomedical research that improves human health, as well as educating and training future generations of leading biomedical scientists and health professionals.
Dr. Li is a Georgia Research Alliance Eminent Scholar in Inflammation & Immunity and Professor of Biomedical Sciences. He joined the university in 2011 as founding director of the Center for Inflammation, Immunity & Infection.
M.D., Medicine, Qingdao University School of Medicine, Qingdao, China,
Ph.D., Biomedical Sciences, University of California, San Francisco, CA. USA
Inflammation, Innate Immunity and infections
Inflammation is a hallmark of many serious human inflammatory diseases, including infectious diseases, chronic obstructive pulmonary diseases, otitis media, asthma, arthritis, inflammatory bowel disease, atherosclerosis and cancer. We primarily focus on understanding the molecular basis of inflammatory diseases and further developing novel anti-inflammatory therapeutic agents.
Appropriate inflammation is a protective host defense response to remove the injurious stimuli as well as initiate tissue healing and repair process. However, overactive inflammation is detrimental to the host, leading to inflammatory diseases. Thus, inflammation must be tightly regulated. In contrast to the positive regulation, inducible negative feedback regulation plays an important role in preventing overactive inflammation. Understanding the molecular mechanisms underlying tight regulation of inflammation will lead to development of novel anti-inflammatory strategies. Moreover, because inflammation is a complex biological response of the body to harmful stimuli, interdisciplinary collaborative efforts would be critical for fully understanding the molecular pathogenesis and thus accelerating the successful development of novel therapeutics.
In the Lab
In my laboratory, multidisciplinary approaches have been undertaken. Those approaches include molecular genetics, cell biology, biochemistry, molecular biology, immunology, chemical biology, pharmacology, functional genomics and proteomics as well as transgenic animals. Currently, we are focusing on the following research areas:
- Inducible Negative Feedback Regulation of Inflammation
We recently found that CYLD, a deubiquitinase, acts as an inducible negative feedback regulator for inflammation. Our studies provide novel insights into the tight regulation of inflammation and may lead to the indentification of novel therapeutic targets. Our future studies will focus on identifying the novel molecular targets of CYLD and the underlying signaling mechanisms involved in inflammatory and infectious disease. We will also investigate the mechanisms by which CYLD is induced.
- Regulation of Host Survival in S. pneumoniae and Influenza Infections
Streptococcus pneumoniae (S.p.) is a major cause of morbidity and mortality worldwide. It is a major cause of community-acquired pneumonia (CAP) and also considered as a significant cause of a secondary infection associated with influenza virus infections. It is unclear why the mortality rate remains very high at early stage. We recently found that CYLD plays a critical role in potentiating the S. pneumoniae-induced lethality. We are currently focusing on investigating the molecular targets and the underlying signaling mechanisms by which CYLD regulates S. pneumoniae-induced lethality.
- Regulation of Mucus Overproduction in Bacterial Infections
Mucus overproduction is a hallmark of upper respiratory tract infections including COPD and otitis media. How mucus is up-regulated remains largely unknown. We recently have identified several positive signaling pathways involved in mucus overproduction. We are currently focusing on determining the negative regulators involved in preventing overactive mucus overproduction and further exploring their translational potential.
- Development of Novel Therapeutic Agents for Inflammatory and Infectious Diseases
Taking advantage of drug repositioning strategy, we recently discovered that Vinpocetine, a well-known natural product, acts as a potent anti-inflammatory agent. Vinpocetine was originally discovered nearly 30 years ago and has been approved for other clinical applications. Its already approved excellent safety and toxicity profile will significantly reduce clinical trial risk and time as well as the cost for drug development. We are currently working on further developing Vinpocetine into an anti-inflammatory therapeutic agent. In addition, we are also working on developing novel therapeutic agents for inhibiting mucus overproduction and reducing lethality.
- Lee BC, Miyata M, Lim JH, Li JD. Deubiquitinase CYLD acts as a negative regulator for bacterium NTHi-induced inflammation by suppressing K63-linked ubiquitination of MyD88. Proc Natl Acad Sci USA. (Epub ahead of print). 2015
- Miyata M, Lee JY, Susuki-Miyata S, Wang WY, Xu H, Kai H, Kobayashi KS, Flavell RA, Li JD. Glucocorticoids suppress inflammation via the upregulation of negative regulator IRAK-M. Nature Communications. 6:6062, 2015
- Susuki-Miyata S, Miyata M, Lee BC, Xu H, Kai H, Yan C, Li JD. Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi. Proc Natl Acad Sci USA. 112(14):E1800-9, 2015
- Lee JY, Komatsu K, Lee BC, Miyata M, O’Neill Bohn A, Xu H, Yan C, Li JD. Vinpocetine inhibits Streptococcus pneumoniae-induced upregulation of Mucin MUC5AC expression via induction of MKP-1 phosphatase in the pathogenesis of otitis media. J Immunol. PubMed PMID: 25972475, May 13, 2015
- Komatsu K, Lee JY, Miyata M, Hyang Lim J, Jono H, Koga T, Xu H, Yan C, Kai H, Li JD. Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD. Nature Communications. 9;4:1684. doi: 10.1038/ncomms2674, 2013.
- Lim JH, Jono H, Komatsu K, Woo CH, Lee J, Huang Y, Zhang W, Park SH, Kim YI, Choi YD, Shen H, Heo KS, Xu H, Bourne P, Koga T, Xu H, Yan C, Chen LF, Feng XH, Li JD. CYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt. Nature Communications. 3:771. doi: 10.1038/ncomms1776, 2012.
- Xu, X, Woo CH, Steere RR, Lee BC, Huang YX, Wu J, Pang J, Lim JH, Xu H, Zhang W, Konduru AS, Yan C, Cheeseman MT, Brown SD, Li JD. EVI1 acts as an inducible negative-feedback regulator of NF-κB by inhibiting p65 acetylation. J Immunol. 188:6371-80, 2012
- Lee J, Komatsu K, Lee BC, Lim JH, Jono H, Xu H, Kai H, Zhang ZJ, Yan C, Li JD. Phosphodiesterase 4B mediates extracellular signal-regulated kinase-dependent up-regulation of mucin MUC5AC protein by Streptococcus pneumoniae by inhibiting cAMP-protein kinase A-dependent MKP-1 phosphatase pathway. J Biol Chem. 287:22799-811, 2012
- Jeon KI, Xu X, Aizawa T, Lim JH, Jono H, Kwon DS, Abe JI, Berk BC, Li JD*, Yan C*. Vinpocetine inhibits NF-kB-dependent inflammation via an IKK-dependent but PDE-independent mechanism. Proc Natl Acad Sci U S A. 107:9795-800, 2010. *Corresponding authors.
- Ishinaga H, Jono H, Lim JH, Komatsu K, Xu X, Lee J, Woo CH, Xu H, Feng XH, Chen LF, Yan C, Li JD. Synergistic induction of NF-kB by TGF-b and TNF-a is mediated by PKA-dependent RelA acetylation. Biochem J. 417:583-91, 2009
- Ha UH, Lim JH, Kim HJ, Wu W, Jin S, Xu H, Li JD. MKP1 regulates the induction of MUC5AC Mucin by pneumoniae Pneumolysin by inhibiting the PAK4-JNK signaling pathway. J Biol Chem. 83:30624-31, 2008.
- Lim JH, Ha UH, Woo CH, Xu H, Li JD. CYLD is a crucial negative regulator of innate immune response in Escherichia coli Cell Microbiol. 10:2247-56, 2008.
- Koga T, Lim JH, Jono H, Ha UH, Xu H, Ishinaga H, Morino S, Xu X, Yan C, Kai H, Li JD. Tumor suppressor CYLD acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling. J Biol Chem. 283:12546-54, 2008.
- Lim JH, Stirling B, Derry J, Koga T, Jono H, Woo CH, Xu H, Ha UH, Andalibi A, Feng XH, Briles DE, Zhu, H., Huang, Y, Zhang, W, Weng, X, Yin, Z, Davis RJ, Flavell RA, Li JD. Tumor Suppressor CYLD Acts as a Crucial Regulator of Acute Lung Injury in Lethal Streptococcus pneumoniae Immunity, 27(2):349-60, 2007.
- Ishinaga, H, Jono H, Lim JH, Kweon SM, Xu H, Ha UH, Xu H, Koga T, Yan C, Feng XH, Chen LF, & Li J.D. TGF-b Induces p65 Acetylation to Enhance Bacteria-induced NF-kB Activation. EMBO J, 26, 150-1162, 2007.
- Ha,U.H., Lim, J.H., Jono, H., Srivastava, A., Malley, R., Pagès, G., Jacques Pouysségur, P. & Li J.D. A Novel Role for IKKa and IKKb in ERK-dependent Innate Mucosal Defense Response against Streptococcus pneumoniae. J Immunol. 178, 1736-1747, 2007.
- Mikami F, Lim JH, Ishinaga H, Ha UH, Gu H, Koga T, Jono H, Kai H, Li JD. Li JD. TGF-b-Smad3/4 Signaling Pathway Acts as a Positive Regulator for TLR2 Induction by Bacteria via a Dual-mechanism Involving Functional Cooperation with NF-kB and MAPK Phosphatase 1-dependent Negative Cross-talk with p38 MAPK. J Biol. Chem. 281, 22397-22408. 2006.
- Yoshida, H, Jono, H, Kai, H, Li JD. The tumor suppressor CYLD acts as a negative regulator for toll-like receptor 2 signaling via negative cross-talk with TRAF6 and TRAF7. .J Biol Chem. 280:41111-41121, 2005.
- Mikami, F, Gu, H, Jono, H, Andalibi, A, Kai, H, Li JD. Epidermal growth factor receptor acts as a negative regulator for bacterium nontypeable Haemophilus influenzae-induced Toll-like receptor 2 expression via an Src-dependent p38 mitogen-activated protein kinase signaling pathway. J Biol Chem. 280:36185-94, 2005
- Watanabe, T., Jono, H., Han, J., Lim, D.J. and Li, J.D. Synergistic Activation of NF-kB by Nontypeable Haemophilus influenzae and Tumor Necrosis Factor-a. Proc Natl. Acad. Sci. USA, 101:3563-8, 2004.
- Jono, H, Lim, JH, Chen, L.F. Xu, H, Trompouki, E., Pan, ZK, Mosialos, G, Li, J.D. NF-kB Is Essential for Induction of CYLD, the Negative Regulator of NF-k J. Biol. Chem. (Accelerated Publication) 279, 36171-36174, 2004.
- Jono, H., Xu, H., Kai, H., Lim, D.J., Kim, Y.S., Feng, X.H. and Li, J.D. TGF-b-Smad Signaling Pathway Negatively Regulates Nontypeable Haemophilus influenzae-induced MUC5AC Mucin Transcription via MAPK Phosphatase-1-dependent Inhibition of p38 MAPK. J Biol. Chem. 278, 27811-27819, 2003.
- 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 enhances nontypeable Haemophilus influenzae-induced expression of toll-like receptor 2. J Biol. Chem. 277:47444-47450, 2002.
- 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-b-Smad Signaling Pathway Cooperates with NF-kB to Mediate Nontypeable Haemophilus influenzae-induced MUC2 Mucin Transcription. J Biol. Chem. 277:45547-45557, 2002.
- 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.
- 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.
- 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.
Jian-Dong Li, M.D., Ph.D.
Professor & Director
Institute for Biomedical Sciences
Georgia Research Alliance Eminent Scholar
Georgia State University
Petit Science Center, Room 714
100 Piedmont Avenue
PO Box 5090
Atlanta, GA 30302-5090
E-mail: [email protected]