(Verbatim) One important unmet medical need is the effective treatment of inflammatory processes in cardiovascular disease, inflammation, and autoimmune diseases. At the moment these diseases are treated with drugs that have inadequate safety profiles and limited efficacy. Only recently several novel classes of anti-inflammatory drugs with a more specific profile have been released. Our goal is to determine which aspects of inflammation are mediated by the Ets transcription factor ESE-l, with the notion that understanding the role of ESE-1 in inflammation may ultimately lead to validation of ESE-1 as an important drug target. ESE-1 has previously been implicated in the regulation of epithelial-specific genes, and under normal physiological conditions ESE-1 expression is restricted to cells of the epithelial cell lineage. We now provide strong evidence for a novel, unexpected function for ESE-1 in inflammation. Strikingly, ESE-1 is expressed in the synovium of rheumatoid arthritis patients, in the vasculature during endotoxemia, and ESE-1 expression is rapidly and transiently induced in several cell types associated with inflammation in response to inflammatory stimuli such as IL-1beta, TNF-alpha, and endotoxin. Induction of ESE-1 expression by pro-inflammatory stimuli is dependent on activation of the NF-KB p50 and p65 family members which induce ESE-l expression via a high affinity NF-kB binding site within the ESE-1 promoter. Using cDNA microarrays we have identified several inflammation response genes as downstream targets for ESE- 1 including MMP-1, MMP-13, Fas, DR5, NOS-2, and COX-2. The induction by pro-inflammatory stimuli of at least two of these genes, NOS-2 and COX-2, depends heavily on ESE-1 induction. Thus, our hypothesis is that ESE-1 is a novel mediator of the inflammatory response that plays a critical role in the regulation of a whole set of inflammatory response genes and contributes to inflammatory processes in inflammatory diseases.
The aim of this proposal is to evaluate the role of ESE- 1 in inflammation, using the murine chronic granulomatous tissue air pouch model as a model for one type of inflammation and microarray analysis to determine biological pathways regulated by ESE-1. Thus, the specific aims are:
Specific Aim #1. Is ESE-1 a critical and direct regulator of ESE-1 inducible target genes? Specific Aim #2. Which part of the inflammatory transcriptional program is due to ESE-1 expression? Specific Aim #3. Does ESE-1 play a role in chronic inflammation? Elucidation of the function of ESE-1 in inflammation will provide exciting opportunities to test the hypothesis that ESE- 1 is a new therapeutic target for anti-inflammatory drug development.
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