Discovery of Therapeutics for Ricin Toxicosis

摘要

Ricin a type II ribosome inactivating protein (a heterodimeric glycoprotein containing two subunits joined together by a disulfide bond) is a biological toxin with a history of use as a weapon of war and bioterrorism. Biological toxins act in concert with various (mostly unknown) host proteins; specific host proteins are essential for toxin action. In an effort to identify possible targets for pharmaceutical intervention that may lead to an effective treatment for ricin toxicosis this study investigates the effects of inactivating specific host proteins and cellular response when exposed to ricin. Specifically 278 genes were selected for challenge based on the criteria developed by Lexicon Genetics to identify genes that might encode pharmaceutically tractable proteins. A full phenotypic analysis of all knockout mouse lines (278) was performed and fibroblast cell cultures were established for all 278 KO lines. A kill curve was established for the mouse fibroblast cells and the fibroblast cell cultures were challenged in triplicate (3 separate homozygous knockout mice for each KO line) with ricin at different points in the curve. Through a cooperative research and development agreement (CRDA) with investigators at USAMRIID specific whole animal gene knockout models will also be made available for testing of modified responses to ricin toxin; this task awaits approval from the USAMRMC Animal Care and Use Review Office (ACURO). A 12-month extension of the performance period (to December 14 2006) was granted in December 2005 to allow time for breeding and shipping mouse lines to USAMRIID.