EXCEED THE SPACE PROVIDED. Transmissible Encephalopathies (TSEs) are caused by a group of related viruslike agents that cause neurodegeneration in sheep, humans, cows and wild animals. Some strains of these agents have developed increased virulence, as evidenced by their epidemic spread. This application continues to exploit different agent strains in our animal models, as well as in our new cell culture models, to further clarify agent-specific properties. We shall compare human CJD, sheep scrapie, and bovine BSE agents. We have found new ways to define individual agent strains: 1) through the use of rapid interference bioassays in vitro, 2) through mouse studies to determine if interference in vitro and in vivo are of comparable strength, and 3) through an analysis of host cell mRNA responses to different agent strains. Host mRNA responses to infection are far simpler in cell cultures than in brain. Our broad aim is to uncover agent properties that have predictive value for understanding the prevention and spread of emergent and epidemic TSE agents in nature. Such studies should also shed light on the evolution and the 'relatedness' of a variety of TSE agents. We will also develop high throughput live cell assays for infectivity in order to pave the way for systematic analyses of agent properties. Such systematic analyses are not feasible in animals. After culture assays are standardized we will analyze the cellular residence of the infectious agent in plasma and other cell membranes, in association with endogenous viral particles, and under several disruption and decontamination conditions. Rapid cell infectivity assays can open the study of TSEs, and provide new strategies for both preclinical diagnosis and prevention. PERFORMANCE SITE ========================================Section End===========================================
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