# Regulation of Proteasome Capacity

> **NIH NIH R35** · FRED HUTCHINSON CANCER CENTER · 2021 · $177,128

## Abstract

PROJECT SUMMARY
Coordinated regulation of protein synthesis, trafficking, post-translational modification and
degradation is a basic requirement for cellular function. Targeted protein degradation in
eukaryotic cells is largely carried out by the proteasome. The proteasome allows dynamic
regulation of protein stability and enforces protein quality control by removing defective
proteins. Importantly, demand for protein degradation by the proteasome within individual
cells can vary due to endogenous signals or exogenous stressors. Thus, condition-specific
regulation of proteasome capacity to maintain adequate, but avoid excessive, protein
degradation is needed to ensure normal development and physiology. Failure to appropriately
regulate the proteasome is implicated in disease. For example, deficient proteasome capacity is
associated with neurodegenerative conditions, whereas proteasome levels and activity are
often elevated in cancerous cells. We do not understand how cells dynamically maintain
appropriate proteasome capacity to meet changing cellular needs. Critically, we do not
understand how the failure or hyperactivity of these mechanisms contributes to disease. Here I
propose a forward genetic approach in C. elegans to discover the factors that control
proteasome capacity, understand how they work at the molecular level, uncover their roles in
normal development, and begin to identify how they may mitigate or contribute to disease. We
will (1) use simple GFP-based reporter assays to perform large-scale genetic screens that will
comprehensively identify proteasome capacity regulators and (2) characterize novel
proteasome regulators we have discovered through these screens. (3) We will uncover how
alterations to specific proteasome subunits differentially alter protein degradation capacity,
development, and proteasome inhibitor resistance. This work will improve our understanding
of the fundamental cellular mechanisms that regulate proteasome capacity in a whole animal
context. In the long-term, these insights will form the conceptual basis for pharmacological
interventions that improve human health via modulation of cellular protein degradation
capacity.

## Key facts

- **NIH application ID:** 10641997
- **Project number:** 6R35GM142728-02
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Nicolas John Lehrbach
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $177,128
- **Award type:** 6
- **Project period:** 2021-08-03 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10641997

## Citation

> US National Institutes of Health, RePORTER application 10641997, Regulation of Proteasome Capacity (6R35GM142728-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10641997. Licensed CC0.

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