Early Host Responses to Prion Infection: Development of In Vivo and In Vitro Assays

摘要

The fist goal was to identify changes in mRNA expression and in plasma glycoproteins that are induced by prion infection in mice. The unusual nature of prion disease prompted a systems approach to identify networks specifically perturbed by prion infections and to determine which perturbations are essential for various aspects of the disease. We tracked changes in gene expression in brain and spleen for two different prion strains and five different lines of mice over their entire incubation periods. A novel approach identified shared differentially expressed genes (DEGs) that were integrated with the kinetics of PrPSc accumulation, pathology, and protein-protein interaction databases to construct prion disease-specific, dynamic protein networks. A Prion Disease Database web site will share these data. The second goal was to determine whether CNS stem cells could provide an in vitro assay for prion infection. We have shown that CNS-stem cell lines mirror the genetic susceptibility of the mice from which they were derived. Cell lines from PrP over expressing mice can detect high dilutions (10-8) of RML prions much more rapidly and economically than mouse bioassays.