P20, 'MOLECULAR SHORTSTOP' FOR INFLAMATORY LUNG DISEASES

描述：（改编自研究者摘要）初步研究 气道上皮细胞炎症反应的机制 表达囊性纤维化缺陷，发现正常气道 当用TNF刺激时，上皮细胞关闭IL-6和IL-8的产生 通过增加p20的产生， 因子C/EBP β（NF-IL 6），其抑制由完整的 长度C/EBP β蛋白。与此相反，气道上皮细胞表达 CF缺陷不会关闭这些促炎细胞因子的产生， 用TNF刺激并且不增加p20的产生。C/EBPbeta是一个 普遍存在的转录因子，并被认为在 调节炎症反应。如果p20和 C/EBP β合成可推广到其他疾病， 炎症，那么p20可能是一种有效的和通用的抗炎剂 其可以作为蛋白质或基于基因的治疗剂递送 剂据推测，p20，转录的截短形式， 因子C/EBP β（也称为NF-IL 6）是一种有效的炎症抑制剂 在各种肺细胞类型，并将是一种有效的抗炎 治疗几种肺部疾病，其特征在于 炎症反应。在该计划的第一阶段，建议：1） 确定是否用质粒表达载体转染肺细胞 含有由CMV启动子驱动的编码p20的基因（pCMVp 20）将 减弱TNF或IL-1刺激的IL-6和IL-8的产生; 2）发展 使用脂质体在细胞内递送p20蛋白的方法 递送系统，并确定蛋白质的递送是否会减弱 TNF或IL-1刺激IL-6和IL-8的产生; 3）确定是否 可以通过以下方式实现p20的细胞内递送和抑制活性 产生由p20和12个氨基酸组成的重组融合蛋白 “膜转位多肽”已经显示能够护送 其他蛋白质转化成几种细胞类型。这个概念可以提供一个新的 治疗方法的主机炎性肺病，包括 特发性肺纤维化、ARDS、囊性纤维化和哮喘。 拟议商业应用：不可用

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