Our broad, long-term objectives are to understand the fundamental properties and operative mechanisms of infectious prion transmission in animals and humans; how properties change during this process; and whether evolution allows infection of additional species.
Aim 1 explores an underappreciated but important phenomenon. When prions infect a new species, despite replicating they unexpectedly cause no disease, but maintain the ability to kill the original species. We will quantify how much and when such prion replication occurs, and define biochemical and biological properties differentiating these from conventional prions.
Aim 2 will address the related issue of how prion strains are propagated, and how prions manifest dominant and recessive traits. Unlike viral characteristics that are genetically controlled, prions, which lack nucleic acids must employ a different mechanism. We find that dominant and recessive prion traits are controlled at the level of protein-protein interactions. We will monitor molecular events in this process using an innovative approach involving antibodies that discriminate subtle prion differences, in much the same way that geneticists discriminate the actions of alternative genes during disease.
In Aim 3, we will use a powerful new mouse model that recapitulates important aspects of chronic wasting disease (CWD), an emerging epidemic of deer, elk and moose. These mice enable us to study aspects of CWD that account for its uniquely contagious transmission. All three aims employ powerful and innovative approaches including uniquely suited genetically modified mice, cell culture assays, cell-free amplification, and antibodies that distinguish prion variants.
These aims address basic, unresolved issues about how prions function which is important because prion diseases occur as unpredictable epidemics (e.g. mad cow disease), are lethal, and currently incurable. CWD is the only known prion disorder affecting wild animals. Its efficient contagious transmission means that it is rapidly increasing in geographic range. Also CWD continues to affect new cervid (antler-bearing) species. Whether CWD or its evolving forms will spread to other species, or to humans, as was the case for mad cow disease, is currently unknown but of significant importance to public health.
Prions are the proteinaceous infectious agents responsible for various fatal animal and human prion diseases. Although these diseases are rare in humans, the reported animal-to-human transmission of the illness and the increasing prevalence of some animal diseases (e.g. chronic wasting disease (CWD) affecting cervids in North America) present important problems for public health. In this Program Project we will investigate the mechanism of prion replication and the generation, adaptation and evolution of prion strains, the routes of transmission of the disease among animals, the evaluation of the zoonotic potential of CWD, the role of the environment on prion transmission and the development of efficient procedures to detect the infectious agent. The findings generated in this project will contribute to prevent further propagation of existing prion disease and to avoid the emergence of new diseases with potentially disastrous consequences. Moreover, understanding of the many uncertainties surrounding prions will be important to design novel therapeutic strategies, and to clarify the molecular basis of this novel type of infectious agent.
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