P20, 'MOLECULAR SHORTSTOP' FOR INFLAMATORY LUNG DISEASES

P20，炎症性肺病的“分子捷径”

• 批准号: 6076035
• 负责人: KENNETH L BRIGHAM
• 金额: $ 10.69万
• 依托单位: GENERX+, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-20 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6076035
• 关键词: antiinflammatory agents; cystic fibrosis; drug design /synthesis /production; gene therapy; inflammation; interleukin 6; interleukin 8; liposomes; lung disorder; recombinant proteins; respiratory epithelium; transcription factor; transfection; transfection /expression vector

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

描述：（根据研究者的摘要改编）在初步研究中 气道上皮细胞中炎症反应的机制 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，转录的截短同工型 因子C/EBPBETA（NF-IL6），该因子通过完整的转录激活抑制转录激活 长度C/EBPBETA蛋白。相反，表达的气道上皮细胞 CF缺陷不会关闭这些促炎性细胞因子的产生 用TNF刺激，不会增加P20的产生。 C/ebpbeta是一个 无处不在的转录因子，被认为在 调节炎症反应。如果P20和 C/EBPBETA合成可以推广到其他疾病过多的疾病 炎症，然后P20可能是一种有效的一般抗炎药 可以作为蛋白质或基于基因的治疗术传递 代理人。假设P20是转录的截断形式 因子C/EBPBETA（又称NF-IL6）是炎症的有效抑制剂 在多种肺部细胞中，将是一种有效的抗炎 肺部多种疾病的治疗性，其特征是 炎症反应。在该程序的第一阶段期间，提议：1） 确定是否用质粒表达载体转染肺细胞 包含由CMV启动子驱动的P20的基因（PCMVP20）将 减弱TNF或IL-1刺激IL-6和IL-8的产生； 2）开发 使用脂质体在细胞内输送P20蛋白的方法 输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 可以通过细胞内递送和P20的抑制活性来实现 创建由P20和12氨基酸组成的重组融合蛋白 “膜易位多肽”，已显示能够护送 其他蛋白质成几种细胞类型。这个概念可以提供新的 用于多种炎症性肺部疾病的治疗方法，包括 特发性肺纤维化，ARD，囊性纤维化和哮喘。 拟议的商业应用程序：不可用