The diversity of the inflammatory process stems from multiple sources, including the complexity of inflammatory stimuli and cell types, the transmembrane and intracellular signaling processes that occur following stimulation, and the large number of independently regulated genes whose expression is subject to modulation during the process.
The primary objective of our research program is to define the molecular events that control the expression of inducible genes during the initiation and resolution of inflammation. An emerging component of these studies includes consideration of the process of cellular stress, also known as the unfolded protein response or endoplasmic reticulum stress. Collectively our research efforts focus on alterations in transcription and mRNA metabolism that can produce significant changes in levels of inflammatory gene products such as chemoattractant cytokines (chemokines) and mediators of cellular stress. Although the mechanisms that increase inflammatory gene expression are important, it is equally necessary to understand negative regulation of these genes since the expression patterns are transient and inappropriate or prolonged expression often results in substantial tissue injury.
The goals of current projects include: (1) identification of mRNA sequence controlling instability and stimulus-induced stabilization, (2) definition of mechanisms through which mRNA decay is achieved, and (3) characterization of the signaling pathways through which inflammatory and cellular stress pathways communicate with one another.
In other words ...
- Evaluation of mechanisms regulating mRNA half life during inflammatory response
- Role of upstream open reading frames in regulating cellular stress responses
- Signal transduction pathways coupling cell stress and inflammatory response in myeloid cells
Datta, S., Novotny, M., Pavicic, P.G., Zhao, C., Herjan, T., Hartupee, J., and Hamilton, T.A., Interleukin 17 regulates CXCL1 mRNA stability via an AUUUA/Tristetraprolin independent sequence, J. Immunol. 184 1484-1491, 2010.
Zhao, C., Datta, S., Mandal, P., Xu, D., and Hamilton, T., Stress sensitive reguation of IFRD1 mRNA decay is mediated by an upstream open reading frame (ORF), J. Biol. Chem. 285: 8552-8562, 2010.
Hamilton, T.A., Novotny, M., Pavicic, P. J., Herjan, T., Hartupee, J., Sun, D., Zhao, C., Datta, S., Diversity in Post-Transcriptional Control of Neutrophil Chemoattractant Cytokine Gene Expression, Cytokine, 52: 116-122, 2010
Wan, Y., Xiao, H.,, Affolter, J., Kim, T.W.,, Bulek, K., Chaudhur, S., Carlson, D., Hamilton, T., Mazumder, T., Stark, G.R., Thomas, J., Li, X., IL-1 receptor-associated kinase 2 is critical for LPS-mediated post-transcriptional control, J.Biol. Chem. 284: 20041 - 20051, 2009
Hartupee, J., Liu, C., Novotny, M., Sun, D., Xiaoxia Li, and Thomas A. Hamilton. IL-17 Signaling for mRNA Stabilization Does Not Require TNF Receptor-Associated Factor 6, J. Immunol. 182: 1660 - 1666, 2009
Datta S, Biswas R, Novotny M, Pavicic PG Jr, Herjan T, Mandal P and Hamilton TA. Tristetraprolin regulates CXCL1 (KC) mRNA stability. J. Immunol. 180(4):2545-2552, 2008.
Hartupee, J., Li, X., and Hamilton, T.A., IL-1alpha -induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1. J. Biol. Chem. 283:15689-15693 2008
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