Project Summary / Abstract
The broad, long-term goal of my research project is to understand the parameters controlling prion transmission
and evolution within and between species, and ultimately to prevent recurrent epidemics in humans and animals.
Chronic wasting disease (CWD), a burgeoning epidemic in cervids of increasingly uncertain zoonotic potential,
is a particular focus within this general framework. My research group is one of only a handful with the resources
and expertise in transgenic, cell biological, biochemical, molecular genetic and in vitro approaches to study prion
diseases. Our output has exerted a powerful and sustained influence on the field. This application leverages a
longstanding relationship with NINDS which is a feature of my uninterrupted record of NIH funding as an
independent investigator for a period covering 26 years. Since prion studies require long-term experimental
commitments requiring sustained and highly coordinated approaches, this proposal explores the feasibility of an
alternate funding mechanism with improved stability and flexibility leading to improved efficiency which will
enhance our already significant capacity to innovate, conduct transformative research, and capitalize on new
developments. This application is designed to build on the advancing trajectory of our research by addressing
key questions relating to naturally-occurring prion diseases with a particular focus on CWD. We will address the
prevalence, properties and origins of emergent and established CWD strains; explore how strain conformations
and species-specific PrP primary structural differences regulate interspecies prion transmission; investigate the
parameters which stabilize strain phenotypes or promote prion adaptation/evolution; address the roles played
by peripheral compartments and the central nervous system in strain selection/adaptation by the host; ascertain
the risks posed by established and emergent strains to humans; and determine the structural properties of CWD
prion strains at high resolution. The proposed mechanism also provides enhanced opportunities for dedicated
mentoring and supervision of trainees and senior scientists, and to optimize my ability to generate a legacy for
the next generation of independent investigators.