Transmissible spongiform encephalopathies (TSE) are a group of rare neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD) in mule deer and elk. TSE infectivity can cross species barriers. The fact that BSE has infected humans in Great Britain and concerns that CWD may act similarly in the US underscores the importance of understanding TSE pathogenesis and developing effective anti-TSE therapeutics. <P> The precise nature of the infectious agent of the TSE diseases is unknown. Susceptibility to infection can be influenced by amino acid homology between a normal host protein (PrP-sen) and the abnormal proteinase K-resistant form of this protein, PrP-res. <P> Formation of PrP-res is closely associated with infectivity and PrP-res has been hypothesized to be the infectious agent in the TSE diseases. An understanding of how this protein is made is critical for our understanding of TSE pathogenesis and for devising therapeutic strategies to prevent its synthesis. <P> My studies address many different aspects of the TSE diseases at both the molecular and pathogenic level. In particular, my laboratory focuses on: 1) identifying the earliest events which occur during TSE infection, 2) precisely defining the different cellular compartments where PrP-res formation occurs, 3) determining the molecular basis of TSE strains, 4) understanding the pathways of PrP amyloid formation, 5) studying how mutations in PrP influence PrP-res formation in familial forms of TSE disease, and 6) development of effective therapeutic TSE agents. <P> In the last year, we have studied the initial events that occur during TSE infection and found that, independent of species or strain, PrP-res formation initially occurs on the cell surface and not intracellularly. Using newly developed systems of PrP amyloid formation, we have demonstrated that the octapeptide repeat region of PrP affects the rate of PrP amyloid formation by influencing PrP binding. Our PrP fibrillization studies also have allowed us to identify a new pathway of PrP amyloid formation and we have initiated in vivo studies to determine if the PrP amyloid fibrils formed can induce disease. Finally, we are continuing our in vivo experiments of last year to study the efficacy of PrP peptide vaccine approaches to TSE disease.