# Designing Multiscale Mathematical Models to Reveal Mechanisms of Prion Loss in Yeast.

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA, MERCED · 2021 · $43,665

## Abstract

7. Project Summary and Abstract
Proteins must fold into specific three-dimensional shapes to work inside cells. Misfolded proteins are
associated with fatal neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.
Prions are a special class of proteins that may misfold and form aggregates which induce other normally
folded conformers of the same protein to misfold and become incorporated. Prion aggregates are not
easily destroyed, and processes in the cell that usually eliminate misfolded proteins actually break
these aggregates into multiple pieces each of which can cause more misfolding. In mammals, prion
diseases are fatal, but in yeast mild experimental manipulations can result in the complete dissolution
of prion aggregates in some cells. Understanding processes leading to prion aggregate dissolution in
yeast advances our understanding of the forces needed to clear protein aggregates and therefore can
support the identification of possible treatments in mammals. Although essential steps have been taken
to identify key molecular processes leading to prion phenotype reversal for yeast, there is a gap in
knowledge to connect molecular level processes with emergent patterns of prion phenotypes at the
colony level. Moreover, prion phenotype reversal in vivo is hypothesized to be the consequence of the
interaction of multiple, poorly understood molecular processes. The goal of this proposal is to bridge
this gap by developing and experimentally validating multiscale mechanistic computational models of
prion aggregation dynamics that incorporate hypothesized mechanisms of aggregate dissolution driving
prion phenotype reversal at different biological scales. Aim 1, involves the development of an agent-
based, multicellular model of yeast colony growth that incorporates both intracellular dynamics of
protein aggregation as well as cell-cell interactions determining spatial organization of the colony.
Spatial and lineage structure of yeast colonies as well as emergent patterns of prion phenotypes will
be analyzed and compared between model output and experiments. In Aim 2, a differential equations
model of the interaction of multiple molecular chaperones and prion aggregates in both normal and
heat-shock conditions will be developed. Simulations will be conducted to explore the interplay between
multiple molecular chaperones, prion aggregates, heat-denatured aggregates and cell division and
used to characterize the prion clearing efficiency of unique cellular environments.

## Key facts

- **NIH application ID:** 10235133
- **Project number:** 1F32GM139400-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, MERCED
- **Principal Investigator:** Mikahl Banwarth-Kuhn
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $43,665
- **Award type:** 1
- **Project period:** 2022-01-03 → 2022-08-02

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10235133

## Citation

> US National Institutes of Health, RePORTER application 10235133, Designing Multiscale Mathematical Models to Reveal Mechanisms of Prion Loss in Yeast. (1F32GM139400-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10235133. Licensed CC0.

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