The central objective of this Project is to define signaling mediators and transcription factors of critical importance in cytokine activation of vascular endothelial cells (EC). Our specific focus is on TNF-a receptor-ll (p75) and the homeobox protein HOXA9. We have recently shown that both molecules are required for cytokine induction of the EC- leukocyte adhesion molecule E-selectin, as well as other activation genes. We showed that TNF-stimulated leukocyte firm adhesion to EC was dramatically reduced in p75-null mice, but not affected in p55 (the other TNF receptor)-null mice. Both receptors participated in TNF-induced leukocyte rolling and transmigration. Furthermore, both p75 and p55 were required for TNF induction of E-selectin and VCAM-1;whereas, p75 was sufficient for ICAM-1 induction. We also demonstrated that p75-deficiency in apoE-null mice reduced atherosclerotic lesion development. Based on these findings, we hypothesize that p75 activation in EC triggers intra-cellular signaling pathways, not induced by p55, that are essential for TNF-induced pro-inflammatory gene expression in EC. We have also recently shown that the transcription factor HOXA9 is required for TNF induction of E-selectin in EC due to its transient binding to a newly identified Abd-B-like site in the promoter. The TNF signal that leads to association of HOXA9 with the E-selectin pro- moter is triggered by p75 and not p55. We hypothesize that HOXA9 plays a novel role in the activation of EC in res- ponse to inflammatory stimuli. We propose to test our hypotheses by pursuing three aims. The first is to identify TNF- induced, p75-specific signaling pathways and novel p75-induced genes in EC using TNF-treated mouse EC isolated from p55-/-, p75-/- and p55-p75-double null mice. We will also identify TNF-induced binding partners of p75 and determine structural domains in p75 responsible for induced gene expression in EC.
The second aim i s to elucidate the molecular mechanism of HOXA9-mediated E-selectin expression and to identify novel target genes for HOXA9 in EC. We will pursue post-translational modifications of HOXA9 and its possible binding to other obligate transcription factors for E-selectin induction. Gene and promoter array studies will be used to identify novel target genes of HOXA9. In the third aim we will characterize the role of the HOXA9-binding partner protein arginine methyl transferase 5 (PRMT5) in activated EC using biochemical, siRNA-based and pharmacological approaches. We also plan to identify proteins methylated by PRMT5 that may qualify for novel mediators of EC activation.
EC, which line all blood vessels in the body, play a key role in inflammation - a process that underlies many diseases, including atherosclerosis. Our studies will reveal new molecular players in the regulation of inflammation. These players will represent novel targets for the development of anti-inflammatory therapeutics that may be used to treat such diseases as coronary artery disease and rheumatoid arthritis.
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