# Mechanisms of Cellular Maintenance

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $375,430

## Abstract

Abstract
 Numerous animal cell types have extended post-developmental lifespans, necessitating robust
mechanisms for cellular maintenance. Cellular maintenance deteriorates in conditions like metabolic and
neurodegenerative diseases and upon acute or chronic exposure to stressors such as pollution and radiation.
Moreover, decline in cellular maintenance is an evolutionarily conserved pathology of aging. Despite its
significance, our understanding of the fundamental mechanisms underpinning cellular maintenance remains
deficient.
 My lab aims to elucidate how post-developmental cells preserve their integrity and function in vivo. We use
the nematode C. elegans for its powerful genetic and live fluorescent imaging capabilities, and for its suitability
for studying cell biology within the organism’s physiological context. In the next five years, we propose to
investigate two key aspects of cellular maintenance:
 First, within mature cells, proteins and organelles undergo continuous turnover: they are degraded, largely
by lysosomes, and replaced to ensure cellular quality. The mechanisms determining lysosomal degradative
capacity and controlling the rate at which degradative cargoes are sent to the lysosome during steady-state
maintenance are not well understood. Building on research initiated in my independent lab, we will take a
three-pronged strategy to address this gap in knowledge, that will: probe the control mechanisms of an
established regulator of degradative capacity, discover novel regulators of degradative capacity through an
unbiased genetic screen, and develop a new tool to measure homeostatic protein degradation, an indicator of
degradative flux, with high spatial resolution in vivo. At present, effective methods to measure this remain
elusive; the development of this tool will not only enable the experimental interrogation of lysosomal
degradative flux but also facilitate exploration of numerous other cell biology questions.
 Second, cellular maintenance is not fully cell-intrinsic; rather, it is governed by intricate intercellular
signaling that coordinates both maintenance and metabolism across diverse cell types within an animal. The
molecular mechanisms underpinning this coordination are incompletely understood. During my postdoctoral
research, I developed the dauer – a C. elegans alternate organismal state – as an experimental paradigm to
study how cellular maintenance can be dramatically extended via intracellular metabolic signaling. We will
expand on this line of research to discover new understandings of the interplay between cellular maintenance,
organismal metabolism, and metabolic signaling.
 Collectively, this research will bridge existing gaps in our understanding of the intracellular and extracellular
mechanisms of cell maintenance, laying the foundation for designing interventions against cellular
maintenance loss in disease and aging.

## Key facts

- **NIH application ID:** 10936222
- **Project number:** 1R35GM154869-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Claire Elissa Richardson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,430
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936222

## Citation

> US National Institutes of Health, RePORTER application 10936222, Mechanisms of Cellular Maintenance (1R35GM154869-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10936222. Licensed CC0.

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