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Thomas A. Hamilton, Ph.D.Department ChairDepartment of Immunology |
Area of general research interest:
Analysis of mechanisms regulating inflammatory gene expression in mononuclear phagocytes. Analysis of stimulus-dependent control of chemokine and cytokine mRNA stability.
Current program:
- Evaluation of mechanisms regulating stimulus dependent control of mRNA stability during inflammatory response
- Mechanisms operating to regulate inflammatory gene expression in vivo
- Mechanisms of anti-inflammatory cytokine function
Investigators:
- Shyamasree Datta, Research Associate
- Donxu Sun, Research Associate
- Chenyang Zhao, Research Fellow
- Tomasz Jerjan, Research Fellow
- Michael Novotny, Lead technologist
- Paul Pavicic, Senior Research Technologist
- Oge Ndum, MD/PhD Student (CWRU)
- Justin Hartupee, MD/PhD Student (CWRU)
Collaborators:
- Xiaoxia Li, Department of Immunology
- Ganes Sen, Department of Molecular Genetics
Brief Description:
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. These studies focus on alterations in transcription and mRNA metabolism that can produce significant changes in levels of inflammatory gene products, including chemoattractant cytokines (chemokines) and chemokine receptors. The specific genes we have used include the ELR-CXC chemokines that target neutrophils during the early inflammatory response to injury and infection and the chemoattractant receptor gene encoding the formylated peptide receptor (FPR1).
Although the mechanisms that increase chemokine gene expression are important, it is equally necessary to understand negative regulation of these genes, as they exhibit the potential to produce 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 stimuli promote alterations in mRNA decay.
Key References:
Novotny, M., et al, Functionally Independent AU Rich Sequence Motifs Regulate
KC (CXCL1) mRNA.J Biol Chem 280:30166-30174, 2005.
Mandal, P., et al. LPS induces formyl peptide receptor 1 gene expression in
macrophages and neutrophils via transcriptional and post-transcriptional mechanisms.
J Immunol 175:6086-6091, 2005.
Mandal, P. and Hamilton T. Signaling in lipopolysaccharide-induced stabilization of formyl Peptide receptor 1 mRNA in mouse peritoneal macrophages. J. Immunol. 178:2542-2548, 2007.
Hartupee J, et al. IL-17 enhances chemokine gene expression through mRNA stabilization. J Immunol 179:4135-41, 2007.
Qian Y, et al. The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8:247-56, 2007.
Zhao C, Hamilton T. Introns regulate the rate of unstable mRNA decay. J Biol Chem 282:20230-7, 2007.
Datta S, Biswas R, Novotny M, Pavicic PG Jr, Herjan T, Mandal P, Hamilton
TA. Tristetraprolin regulates CXCL1 (KC) mRNA stability. J Immunol
180(4):2545-52, 2008. [PMID: 18250465]
Hartupee J, Li X, Hamilton TA. IL-1alpha -induced NFkappaB activation and
chemokine mRNA stabilization diverge at IRAK1. J. Biol. Chem. 2008;April
(in press).