Research
Fu, Jian, Ph.D.
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Contact: jian.fu@uthct.edu
Education:
Ph.D. 2000, Physiology and Biophysics, University of Alabama at Birmingham
Research Interest:
Cancer immunology; Lung inflammation and injury
Current Projects:
- Modulation of cancer cell-reactive immune responses.
- Mechanisms of lung inflammation and injury.
Research Overview:
Modulation of cancer cell-reactive immune responses. Immunotherapy has shown great promise in cancer treatment. However, resistance of cancer cells to immunotherapy remains a big challenge. Thus, developing new agents that can modulate cancer cell-reactive immune responses is necessary for the improvement of the efficacy of immunotherapy.
Programmed death-1-ligand 1 (PD-L1) is a cell surface protein of B7 family. PD-L1 is one of the two ligands for program death receptor 1 (PD-1), a co-stimulatory molecule that negatively regulates T cell immune responses. It is now well accepted that PD-L1 expression in cancer cells contributes to immunoresistance. The expression of PD-L1 has been detected in a variety of solid tumors but not in normal tissue. Furthermore, PD-L1 expression on carcinomas is correlated with poor clinical prognosis of renal, gastric carcinomas, breast cancers and esophageal cancers. Ligation of PD-L1 expressed on cancer cells to PD-1 expressed on T cells has been shown to suppress T cell activation and proliferation, and induce T cell apoptosis. PD-L1 blockade using PD-L1 antibody was able to induce anti-tumor immunity and inhibit tumor growth. Therefore, increased PD-L1 expression in cancer cells could be an important escape mechanism from the host T cell immunity.
Given the critical role of PD-L1 in cancer cell-reactive T cell immune suppression, blockade of PD-L1/PD-1 pathway could be a valuable approach to improve cancer immunotherapy. Our current projects are to investigate the mechanisms of PD-L1 surface expression in breast cancer cells, and to determine the role of PD-L1-mediated T cell suppression in breast cancer immune evasion. Through our studies, we hope to identify a new class of therapeutic agents that may possess dual functions to inhibit cancer cell growth and boost anti-cancer immunity.
Mechanisms of lung inflammation and injury. Acute lung injury (ALI) is usually associated with excessive pulmonary inflammation. Neutrophil accumulation in the lung plays a crucial role in both the onset and progression of ALI. Production and up-regulation of pro-inflammatory mediators such as ICAM-1, P-selectin, TNF-alpha, and NF-κB have been reported to contribute to LPS-induced lung inflammation. Increased apoptotic signaling has been demonstrated in LPS-induced lung vascular injury. The extensive neutrophil influx to the lung requires pro-inflammatory signals capable of supporting both the early recruitment and persistent influx of neutrophils. The initial recruitment of neutrophils to the lung may require early signals such as the expression of ICAM-1 and P-selectin in lung endothelial cells that mediate neutrophil adhesion and migration across the lung vasculature. Persistent neutrophil influx may require additional mediators such as pro-inflammatory cytokine CXCR4/SDF-1. Despite the considerable progress made in elucidating the pro-inflammatory mediators that contribute to ALI, it is likely that some of the key mediators remain unidentified. The research interest of my lab in this area is to uncover the mechanisms of acute lung inflammation and injury, and to identify new mediators of lung injury that may serve as potential targets for therapeutic intervention.
Selected Papers and Abstracts:
- Zhang P, Su DM, Liang M, Fu J. Chemopreventive agents induce programmed death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated T cell apoptosis. Mol Immunol. 2008 Mar;45(5):1470-6. Epub 2007 Oct 24.
- Liang M, Zhang P, Fu J. Up-regulation of LOX-1 expression by TNF-alpha promotes trans-endothelial migration of MDA-MB-231 breast cancer cells. Cancer Lett. 2007 Dec 8;258(1):31-7. Epub 2007 Sep 14.
- Gao XP, Zhu XD., Fu J, Liu QH, Frey RS, Malik AB. Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation. J Biol Chem. 2007 Mar 2;282(9):6116-25. Epub 2006 Dec 29.
- Low B., Liang M., Fu J. p38 mitogen-activated protein kinase mediates sidestream cigarette smoke-induced endothelial permeability. J Pharmacol Sci. 2007 Jul;104(3):225-31.
- Ge X, Low B, Liang M, Fu J. Angiotensin II directly triggers endothelial exocytosis via protein kinase C-dependent protein kinase D2 activation. J Pharmacol Sci. 2007 Oct;105(2):168-76.
- Yasuda S, Idell S, Fu J, Carter G, Snow R, Liu MC. Cigarette smoke toxicants as substrates and inhibitors for human cytosolic SULTs. Toxicol Appl Pharmacol. 2007 May 15;221(1):13-20. Epub 2007 Feb 28.
- Fu J, Naren AP, Gao XP, Ahmmed GU, Malik AB. Protease-activated receptor-1 activation of endothelial cells induces protein kinase Calpha-dependent phosphorylation of syntaxin 4 and Munc18c: role in signaling p-selectin expression. J Biol Chem. 2005 Feb 4;280(5):3178-84. Epub 2004 Dec 2.
- Ji HL, Jovov B., Fu J., Bishop LR., Mebane HC., Fuller CM., Stanton BA, Benos DJ. Up-regulation of acid-gated Na(+) channels (ASICs) by cystic fibrosis transmembrane conductance regulator co-expression in Xenopus oocytes. J Biol Chem. 2002 Mar 8;277(10):8395-405. Epub 2001 Dec 17.
- Fu J, Ji HL, Naren, AP, Kirk KL. A cluster of negative charged residue at the amino terminal tail of CFTR regulates ATP-dependent channel gating. J Physiol. 2001 Oct 15;536(Pt 2):459-70.
- Fu J, Kirk KL. Cysteine substitutions reveal dual functions of the amino-terminal tail in cystic fibrosis transmembrane conductance regulator channel gating. J Biol Chem. 2001 Sep 21;276(38):35660-8. Epub 2001 Jul 23.
- Naren AP, Boyaka E, Fu J, Villain M, Blalock E, Quick MW., Kirk KL. CFTR chloride channel regulation by an interdomain interaction. Science. 1999 Oct 15;286(5439):544-8.
- Fu J, Scammell JG, Li M. Epidermal growth factor reduces L-type voltage-activated calcium current density in GH4C1 rat pituitary cells. Neuroendocrinology. 1997 Mar;65(3):157-63.
- Wang L., Bhattacharjee A., Fu J, Li M. Abnormally expressed low-voltage-activated calcium channels in beta cells from NOD mice and a related clonal cell line. Diabetes. 1996 Dec;45(12):1678-83.
