# Chaperone-mediated mechanisms of cellular proteostasis

> **NIH NIH R35** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2024 · $386,931

## Abstract

PROJECT SUMMARY
 A broad range of major diseases ranging from diabetes to neurodegenerative
disorders including Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases
have been linked to protein misfolding and aggregation. Normal protein homeostasis
(proteostasis) in the cytosol and nucleus is maintained by networks of factors that
promote protein folding (molecular chaperones) or clearance of terminally misfolded
substrates (ubiquitin-proteasome system (UPS), autophagy). Cells grow and proliferate
under the constant threat of intrinsic and extrinsic proteotoxic stressors including
reactive oxygen species (ROS), exogenous oxidants and reactive electrophiles.
However, the interface between proteostasis and cellular reduction-oxidation (redox)
buffering pathways, namely the thioredoxin and glutathione systems, is not well
understood. Our long-term goal is a comprehensive understanding of the biological roles
of cytoprotective chaperones, the machinery employed to maintain redox balance and
the interplay between them. In this MIRA application we define two independent themes
that define our future research program. In the first line of investigation, we will examine
redox modulation of cytoplasmic spatial protein quality control and degradation,
empowered by our discoveries that the sequestrase Hsp42 accumulates with misfolded
proteins and is required for optimal growth in redox-deficient yeast cells that lack a
functional thioredoxin system. We have also uncovered a new arm of the endoplasmic
reticulum-based unfolded protein response (UPR) pathway that is activated in
thioredoxin-deficient cells and operates independently of the primary UPR transcription
factor Hac1; we will elucidate the mechanism and biological relevance of this alternate
cytoprotective system. The second broad direction will expand our studies of metazoan
chaperone mechanisms with both biochemical and animal-based studies using
Drosophila based on our discovery of a novel intrinsically disordered region (IDR) in fly
and human Hsp110 chaperones with powerful anti-aggregation and anti-amyloid
properties. The work outlined in this proposal will expand on our past successful studies
of cellular redox and protein quality control networks, exploiting tractable yeast and fly
model systems. These results in turn will guide future development of therapeutic
interventions targeting ROS- and protein quality control-based disorders.

## Key facts

- **NIH application ID:** 10814402
- **Project number:** 5R35GM149196-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** KEVIN ANTHONY MORANO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $386,931
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814402

## Citation

> US National Institutes of Health, RePORTER application 10814402, Chaperone-mediated mechanisms of cellular proteostasis (5R35GM149196-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10814402. Licensed CC0.

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