MURINE TRANSGENIC MODELS OF PRION DISEASES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prion diseases, including Creutzfeldt-Jakob disease and kuru, are fatal neurodegenerative disorders that are now of great medical importance because of emergence of "mad cow disease" in Europe and the U.S., and its likely transmission to human beings. These diseases are also of enormous scientific interest because they involve an entirely novel mechanism of biological information transfer: they result from a change in the conformation of an endogenous membrane glycoprotein (PrPC) which converts it into a pathogenic isoform (PrPSc) that is infectious in the complete absence of nucleic acid. The Harris laboratory is interested in understanding prion diseases at the cellular and molecular levels. They are investigating a number of interrelated questions, including: How is PrPC is converted into PrPSc? How are these forms processed and targeted in cells? What other proteins do they interact with? What is the normal function of PrPC? How do prions kill cells, and what forms of PrP are responsible? To address these issues, they utilize several experimental systems including yeast, cultured mammalian cells, and transgenic mice. We employ a wide range of techniques, including cell labeling, protein chemistry, microscopy, DNA microarray analysis, mouse genetics, neuropathology, animal bioassays, and mass spectrometry.