P20, 'MOLECULAR SHORTSTOP' FOR INFLAMATORY LUNG DISEASES

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DESCRIPTION: (Adapted from the Investigator's Abstract) In preliminary studies of the mechanism of the inflammatory response in airway epithelial cells expressing the cystic fibrosis defect, it was found that normal airway epithelial cells turn off production of IL-6 and IL-8 when stimulated with TNF by increasing production of p20, a truncated isoform of the transcription factor C/EBPbeta (NF-IL6) which inhibits transcriptional activation by the full length C/EBPbeta protein. In contrast, airway epithelial cells expressing the CF defect do not turn off production of these pro-inflammatory cytokines when stimulated with TNF and do not increase production of p20. C/EBPbeta is a ubiquitous transcription factor and is thought to play a pivotal role in regulating the inflammatory response. If this imbalance between p20 and C/EBPbeta synthesis can be generalized to other diseases with excessive inflammation, then p20 could be a potent and general anti-inflammatory agent which could be delivered either as a protein or as a gene based therapeutic agent. It is hypothesized that p20, a truncated form of the transcription factor C/EBPbeta (a.k.a. NF-IL6), is a potent general inhibitor of inflammation in a variety of lung cell types and will be an effective anti-inflammatory therapeutic in several diseases of the lungs characterized by dysregulation of the inflammatory response. During Phase I of this program it is proposed: 1) to determine whether transfection of lung cells with a plasmid expression vector containing the gene encoding p20 driven by a CMV promoter (pCMVp20) will attenuate TNF or IL-1 stimulated production of IL-6 and IL-8; 2) to develop methods for delivering the p20 protein intracellularly using a liposome delivery system and determine whether delivery of the protein will attenuate TNF or IL-1 stimulated production of IL-6 and IL-8; 3) to determine whether intracellular delivery and inhibitory activity of p20 can be achieved by creating a recombinant fusion protein consisting of p20 and a 12 amino acid "membrane translocating polypeptide" which has been shown capable of escorting other proteins into several cell types. This concept could provide a new therapeutic approach to a host of inflammatory lung diseases, including idiopathic pulmonary fibrosis, ARDS, cystic fibrosis and asthma. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE