# Cellular Mechanisms and Consequences of Protein Misfolding and Resolution

> **NIH NIH R35** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2022 · $360,074

## Abstract

8. Project Summary/Abstract
Many proteins access, in addition to their native state, an alternative pathway of folding leading
to the formation of amyloid aggregates. Amyloidogenesis has been linked not only to more than
fifty human diseases but also to functions, which benefit the organism. Once arising, the
amyloid state is perpetuated through the incorporation and conformational conversion of native-
state protein, fragmentation of growing complexes and transmission both within and to other
individuals. These central events are modulated by protein sequence and conformation, protein
quality control pathways, and cell biology. Yet, how these contributing factors and processes
intersect to impact organismal physiology is poorly understood, despite a growing appreciation
of the contributions of amyloid to the biology of systems from yeast to man. This current gap in
knowledge is a critical barrier to progress in the field because we are unable to rationally
explain, predict, exploit, and reverse the link between amyloidogenesis and its physiological
effects. Our long-term goal is to bridge this gap by determining how these inputs are balanced
and disrupted to create and cure dynamic phenotypic states. Toward this end, we are exploiting
prions of Saccharomyces cerevisiae as an outstanding and robust model. Sharing many
characteristics with metazoan amyloids, yeast prions are a naturally evolved system in which
the thresholds separating phenotypic states can be accessed, studied, and traversed under
physiologically relevant conditions. We will exploit dichotomies in yeast prion biology, where the
same event yields distinct outcomes in different contexts, as experimental entryways to
elucidate system balance for the most crucial transitions: prion appearance, interference, curing,
and toxicity. Together, our studies will elucidate the molecular basis of proteostatic niches that
allow amyloid to survive or to be lost and will provide a framework for understanding similar
transitions in higher eukaryotes.

## Key facts

- **NIH application ID:** 10470161
- **Project number:** 5R35GM118042-08
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** TRICIA R. SERIO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,074
- **Award type:** 5
- **Project period:** 2016-06-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470161

## Citation

> US National Institutes of Health, RePORTER application 10470161, Cellular Mechanisms and Consequences of Protein Misfolding and Resolution (5R35GM118042-08). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10470161. Licensed CC0.

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