Induction of IKBA gene transcription by nitric oxide

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (Applicant?s abstract): Recent studies suggest that an endogenous free radical, nitric oxide (NO), can attenuate atherosclerosis and vascular inflammation. Although the precise mechanism(s) underlying these anti-inflammatory effects are not fully understood, it may involve modulation of mediators that regulate the inflammatory process. One such mediator is the transcription factor, NF-kB, which is required for the transcriptional induction of pro-inflammatory genes such as cytokines and cellular adhesion molecules. Our laboratory has previously demonstrated that NO inhibits NF-KB activation via the induction of the NF-kB inhibitor, IKBa Thus, determining the mechanism(s) by which NO up regulates IkBa may have important therapeutic implications in vascular inflammation. The overall purpose of this research proposal is to characterize the molecular mechanism(s) by which NO increases 1KB a gene expression. The putative NO-responsive motif(s) within the IkBa gene promoter will be characterized and the transcription factors that bind to the motif(s) will be identified (and cloned, if novel). All of the methods and reagents to accomplish the proposed specific aims are readily available in the sponsor?s laboratory. The results obtained from this work could have enormous therapeutic implications in atherosclerosis and vascular inflammation.