PURIFICATION AND CHARACTERIZATION OF TNF INHIBITOR

TNF 抑制剂的纯化和表征

• 批准号: 3506816
• 负责人: SUSAN C WRIGHT
• 金额: $ 26.17万
• 依托单位: PANORAMA RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-03 至 1994-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3506816
• 关键词: adult respiratory distress syndrome; affinity chromatography; antiinflammatory agents; blood /lymphatic pharmacology; cell adhesion; cell cycle; cellular pathology; cytotoxicity; disease /disorder model; free radicals; guinea pigs; human genetic material tag; human tissue; inflammation; inhibitor /antagonist; laboratory mouse; molecular cloning; nitrogen; protein purification; protein structure function; recombinant DNA; shock; superoxides; tissue /cell culture; tumor necrosis factor alpha

The main objective of this Phase II application is to continue in vitro and preclinical studies to evaluate a potential biologic therapeutic for septic shock. Phase I purified a TNF inhibitor that is homologous to human MRP-8, a molecule of unknown function. It was also discovered that nanomolar concentrations of this peptide could inhibit LPS-induced production of reactive nitrogen intermediates (RNI) by macrophages. Since overproduction of both TNF and RNI is implicated in the pathogenesis of septic shock, this new activity makes MRP-8 even more promising as a treatment for sepsis. Phase II plans are to clone the human gene for MRP-8, express, and purify the recombinant molecule. Purified rMRP-8 will be evaluated in vitro and in vivo models of sepsis and inflammation. In vitro studies will focus on determining RMRP-8's spectrum of activities and analyzing mechanism of action. In vivo studies will evaluate efficacy in mouse models of endotoxemia and sepsis and in a guinea pig model of LPS-induced adult respiratory distress syndrome. The results of these studies will be crucial to determine whether further clinical studies planned for Phase III are warranted.

该二期应用的主要目标是继续在体外和 评估脓毒症潜在生物疗法的临床前研究 震惊。 I期纯化了与人MRP-8同源的TNF抑制剂， 功能未知的分子。 还发现纳摩尔 该肽的浓度可以抑制 LPS 诱导的 巨噬细胞产生活性氮中间体（RNI）。 由于生产过剩 TNF 和 RNI 均与感染性休克的发病机制有关，这 新的活性使得 MRP-8 作为败血症的治疗更有希望。 二期计划是克隆、表达和纯化 MRP-8 人类基因 重组分子。 纯化的 rMRP-8 将在体外进行评估 败血症和炎症的体内模型。 体外研究将集中于 确定 RMRP-8 的活性谱并分析其机制 行动。 体内研究将评估在小鼠模型中的功效 内毒素血症和败血症以及 LPS 诱导的成人豚鼠模型 呼吸窘迫综合征。 这些研究的结果将是 对于确定是否计划进行 III 期临床研究至关重要 是有保证的。