# Aging and organismal proteostasis-Project 4 RM

> **NIH NIH P01** · NORTHWESTERN UNIVERSITY · 2021 · $424,061

## Abstract

Project 4 Summary- Morimoto
Aging leads to proteostasis failure at the organismal level and is associated with the increased risk for
misfolding, aggregation, and neurodegenerative disease. The emphasis of this Project is on organismal
proteostasis, to understand how intertissue regulation of the proteostasis network (PN) between neurons and
non-neuronal tissues of C. elegans. Our goals are to establish how communication between tissues ensures
healthy proteostasis, to identify the basis for failure in quality control in aging, and how expression of Tau,
SOD1, and polyglutamine causes amplification of proteotoxicity directly relevant to neurodegenerative
disease. C. elegans has the advantages of transparency, detailed lineage relationships, and powerful genetic
and molecular tools that are ideal to assess synthesis, folding, the ubiquitin-proteasome and autophagy
lysosome pathway in tissues of wild type animals during normal aging. These results will be compared to
short-and-long lived animals, and exposure to acute (heat shock) and chronic (Tau, SOD1, and polyglutamine)
proteotoxic stress to identify the critical components of the PN that are essential for rapid response and
protection. In C. elegans and other metazoans, the PN is regulated by cell non-autonomous control; for
example, the organismal heat shock response (HSR) is regulated by sensory neurons that control induction of
the HSR and properties of the PN in distal somatic tissues, moreover inducibility of the HSR declines in early
adulthood by signal(s) from germ line stem cells that results in reduced tissue resilience post fecundity. The
Aims are to: (1): Examine the effects of aging and proteotoxic stress on PN composition and properties.
We will use proteostasis reporters (Core B) to assess and quantify folding, transport, and degradation in
different tissues during development and aging, and upon exposure to physiological and proteotoxic stress,
relate PN functionality to PN composition in tissues using cell type-specific transcriptomic profiling and
proteomics (Cores B, C), and establish how the PN adjusts in short-and long-lived animals, (2): Examine how
intertissue stress signaling in aging is affected by Tau, SOD1, and polyglutamine proteins. We will use
genetic approaches to perturb the PN in neurons, muscle, intestine to identify tissue circuits and directionality
of stress signaling across tissues, determine the effects of aging and expression of Tau, SOD1, and
polyglutamine proteins on intertissue communication, and whether PN modulation in sending or receiving
tissues can restore proteostasis against proteotoxicity, and (3): Deploy proteostasis regulators to restore
organismal proteostasis in aging and neurodegeneration. With Core D, we will develop strategies for PN
modulation by small molecule Proteostasis Regulators to prevent proteostasis failure during aging and
proteotoxicity of Tau, SOD1, and polyglutamine. The targets will be validated using genetic approaches (RN...

## Key facts

- **NIH application ID:** 10183117
- **Project number:** 5P01AG054407-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** RICHARD I MORIMOTO
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $424,061
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10183117

## Citation

> US National Institutes of Health, RePORTER application 10183117, Aging and organismal proteostasis-Project 4 RM (5P01AG054407-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10183117. Licensed CC0.

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