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An Improved Expression Vector to Create Transgenic Mice for Prion Research


Prions are transmissible pathogenic agents responsible for fatal neurodegenerative diseases such as Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, and bovine spongiform encephalopathy (BSE) in cattle. These disorders are characterized by the conversion of the host-encoded cellular prion protein (PrPc) into an abnormally folded and infectious isoform (PrPSc) that accumulates in the brain and causes disease. <P> Transgenic mice are important tools to study prion diseases. Due to the expression vectors in use, current transgenic mouse models are imperfect and show PrPc-expression profiles dissimilar from wild-type (wt) mice. <P> Our long-term goal is to develop a transgenic mouse model in which the PrPc-expression profile is identical to wt PrPc expression. An authentic mouse model is a prerequisite to the development of accurate protocols that prevent the transmission of infectious prions and attenuate or cure the disease. <P> Our specific hypothesis is that a transgenic expression vector based on a mouse bacterial artificial chromosome (BAG) clone will include all genetic regulatory elements necessary to drive a locus-independent expression of PrPc that is indistinguishable from wt mice.<P> The specific aims are to: 1. Develop a new vector for PrPc expression in transgenic mice. Based on a fully sequenced mouse BAG clone, we will generate an array of truncated vectors that can drive PrPc expression in transgenic animals. We will introduce a cloning site into this vector that will allow replacing the open reading frame (ORF) of the prion protein gene (Prnp) with alternative sequences. <P> 2. Create and identify transgenic mice that have a PrPc-expression profile identical to wt mice. We will use the expression vectors cloned in Specific Aim #1 to create transgenic mice through pronuclear microinjection into oozytes from Prnp-ablated mice. We will create and identify animals that have a PrPc- expression profile that is indistinguishable from wt mice. <P> 3. Characterize the incubation time and PrPSc profile in transgenic mice after infection with prions. <P> Once we have identified a vector that gives rise to transgenic animals that have a wt PrPc-expression profile, we will infect these animals with prions. We will determine the incubation time and the PrPSo profile generated in these mice and validate this new mouse model by comparison to wt mice.

Tamguney, Gultekin
University of California - San Francisco
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