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.