Our long term goal is to pioneer new approaches that limit the harmful effects of inflammatory processes (such as those observed in periodontitis), while preserving the beneficial effects (e.g. tissue repair, resolution of infections). The studies we propose here build upon our recent results. Most notably, we discovered transcriptional regulators of inflammatory cytokines, including the pivotal cytokine tumor necrosis factor-a (TNF-a). TNF is tightly regulated;its overproduction can be lethal, as in septic shock syndrome. In previous studies we discovered a new transcription factor, Lipopolysaccharide-lnduced TNF-Alpha Factor (LITAF), which regulates TNF gene expression. More recently, we found another newly identified transcription factor STAT6B that binds to LITAF, and together this complex enhances the expression of a whole group of pro-inflammatory cytokines: GRO, IL-1a, RANTES, TNF-a, IFN-y, MCP-1, and MCP-2, VEGF as well as the anti-inflammatory cytokine IL-10.
The Specific Aims of this proposal are designed to test the hypotheses that (1) LITAF stimulates the inflammatory response and together with STAT6B this response is largely amplified and (2) that STAT6B alone upregulates VEGF while together with LITAF, VEGF is inhibited. The proposed identification of the phosphorylation-dephosphorylation processes governing LITAF and STAT6B activity will be instrumental in understanding the cell trafficking of these molecules (Aim 1). The minimal and specific DNA sequence responsible for protein binding to LITAF on MCP1 promoter, and the role of LITAF-STAT6B (Aim 2), will allow identification of other promoters that may be targeted by these proteins. It will also permit evaluation of the role of LITAF and STAT6B in the regulation of their respective genes. To accomplish this, we will engineer specific mutations within the human MCP promoters, to reveal the exact DNA binding sequence controlled by LITAF and the role of STAT6B. Coupling the mutant promoters to reporter genes will allow us to assess whether these mutant promoters fail to be activated by LITAF and by the LITAF-STAT6B complex. Mutant LITAF and STAT6B proteins (muteins) will be designed to identify both the DNA-binding and trans-activation domains (Aim 2). and this data will provide critical insights for elucidating promoter interactions in other genes. A similar approach will be taken for STAT6B and VEGF to determine the minimal VEGF promoter sequence and STAT6B peptide involved in these DNA-protein interactions. The role of LITAF-STAT6B complex in inhibiting VEGF will be actively pursued in the same context (Aim 3). The success of LITAF knockout mice along with our proposal of generating STAT6B-deficient mice will build upon the results of Aims 1 and 2 and 3 to evaluate the hypothesis that the LITAF and STAT6B gene products, through regulation of cytokine activity, play an important role in the development of inflammatory diseases, including periodontitis (Aims 3).
Aim 4 will expand our recent finding linking STAT6B to VEGF and angiogenesis. We intend to test how angiogenesis can be modulated by STAT6B and the LITAT-STAT6B complex. Our discovery of LITAF and the novel protein STAT6B, factors that help regulate cytokine transcription and angiogenesis, will serve as new tools to dissect the complex mechanisms that mediate cytokine expression in various inflammatory conditions, including periodontitis and vessel formation. Our goal is to develop pharmacological approaches aimed at modulating inflammation and angiogenesis.
|Tang, Xiaoren; Amar, Salomon (2016) Kavain Involvement in LPS-Induced Signaling Pathways. J Cell Biochem 117:2272-80|
|Tang, Xiaoren; Amar, Salomon (2016) Kavain Inhibition of LPS-Induced TNF-Î± via ERK/LITAF. Toxicol Res (Camb) 5:188-196|
|Tang, Xiaoren; Amar, Salomon (2015) p53 suppresses CCL2-induced subcutaneous tumor xenograft. Tumour Biol 36:2801-8|
|Bertolo, Cristina; Roa, Sergio; Sagardoy, Ainara et al. (2013) LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. Br J Haematol 162:621-30|
|Tang, Xiaoren; Yang, Yu; Yuan, Huaiping et al. (2013) Novel transcriptional regulation of VEGF in inflammatory processes. J Cell Mol Med 17:386-97|
|Liu, Bo; Faller, Lina L; Klitgord, Niels et al. (2012) Deep sequencing of the oral microbiome reveals signatures of periodontal disease. PLoS One 7:e37919|
|Tang, X; Asano, M; O'Reilly, A et al. (2012) p53 is an important regulator of CCL2 gene expression. Curr Mol Med 12:929-43|
|Tang, X; O'Reilly, A; Asano, M et al. (2011) p53 peptide prevents LITAF-induced TNF-alpha-mediated mouse lung lesions and endotoxic shock. Curr Mol Med 11:439-52|
|Tang, Xiaoren; Yang, Yu; Amar, Salomon (2011) Novel regulation of CCL2 gene expression by murine LITAF and STAT6B. PLoS One 6:e25083|
|Yuan, Huaiping; Gupte, Rohit; Zelkha, Sami et al. (2011) Receptor activator of nuclear factor kappa B ligand antagonists inhibit tissue inflammation and bone loss in experimental periodontitis. J Clin Periodontol 38:1029-36|
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