This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inflammatory and autoimmune diseases, such as asthma and rheumatoid arthritis, are characterized by the accumulation of immune cells that cause tissue damage in response to a complex array of secreted signaling molecules. Two cytokines thought to be critical mediators of inflammation are IL-1b and TNF-a. These cytokines exert distinct yet overlapping effects on target tissues, primarily by altering patterns of gene expression. IL-1b and TNF-a control gene expression by binding to distinct cell surface receptors, whereupon multiple protein kinase cascades are activated. We propose a pharmacological approach to study these complex signaling pathways. Our idea derives from the recent discovery that a marine natural product, ceratospongamide, potently inhibits gene expression induced by IL-1b with an IC50 of 32 nM. We seek to elucidate its mechanism of action. Ceratospongamide is a macrocyclic heptapeptide that is conformationally constrained by two additional rings (thiazole and oxazoline) formed by the cyclization of cysteine and threonine side chains onto the peptide backbone. We will synthesize ceratospongamide and derivatives that will enable the identification of its cellular targets. both radiolabeled and immobilized derivatives for affinity purification will be synthesized using modern synthetic methodology. Mass spectrometry measurements obtained at the UCSF Facility will be essential for two reasons: (1) characterizing synthetic intermediates and (2) identifying ceratospongamide's protein target.
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