# Project 1: Modeling the Mechanisms of Prion Transmission, Strain Selection, Mutation and Species Barrier in Transgenic Mice

> **NIH NIH P01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $429,352

## Abstract

Our broad, long-term objectives are to are to decipher the mechanisms by which infectious
prions replicate, encode strain information, and evolve to acquire new properties. We
propose four Specific Aims to address our central hypothesis that incompletely adapted
prion strains are comprised of poorly optimized ensembles of PrPSc quasi species
conformers that evolve under selective pressure towards states of enhanced stability and
pathogenicity. Our particular focus is chronic wasting disease (CWD), an uncontrollable
contagious epidemic of cervids of uncertain zoonotic potential. Using genetically
engineered CWD-susceptible mice, cultured cells, cell free amplification, and antibodies
recognizing defined conformation-dependent PrP epitopes, Aim I will address the
mechanism of adaptation of unstable emergent CWD prions in response to physical and
chemical constraints. In Aim II we will address the hypothesis that that residue 226 and
other cervid PrP polymorphisms influence selection of distinct portfolios of CWD strain
conformers with different adaptive potentials. Using gene targeted mice expressing
physiologically controlled levels of PrP variants and in vitro systems for prion replication,
we will characterize the properties of strains propagated in these backgrounds and explore
whether interference between them affects selection and adaptation of CWD. In Aim III,
we will assess the properties of emergent Norwegian moose and reindeer CWD strains
experimentally propagated in deer and compare with established North American CWD.
Aim IV will address an unmet need in the field of significant importance, namely the paucity
of model systems and tools for studying human prions. Using newly generated gene
targeted mice expressing physiological levels of human PrP and novel approaches to
derive susceptible human neuroblastoma cells, we will assess the zoonotic potential of
emergent CWD strains and their adapted derivatives propagated in different cervid PrP
backgrounds. Our ultimate goal is to assess and manage the risk posed to humans from
continually evolving prions, specifically those causing CWD, by understanding the means
by which they propagate and exist as heritable strains with protean host range properties
that adapt and evolve under selective pressure.

## Key facts

- **NIH application ID:** 10332507
- **Project number:** 2P01AI077774-11
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Glenn C Telling
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $429,352
- **Award type:** 2
- **Project period:** 2008-08-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10332507

## Citation

> US National Institutes of Health, RePORTER application 10332507, Project 1: Modeling the Mechanisms of Prion Transmission, Strain Selection, Mutation and Species Barrier in Transgenic Mice (2P01AI077774-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10332507. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*