# Regulation of Proteasome Capacity

> **NIH NIH R35** · FRED HUTCHINSON CANCER CENTER · 2024 · $27,818

## Abstract

Project Summary/Abstract
(From the original application) 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:** 11036057
- **Project number:** 3R35GM142728-05S1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Nicolas John Lehrbach
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $27,818
- **Award type:** 3
- **Project period:** 2021-08-03 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11036057

## Citation

> US National Institutes of Health, RePORTER application 11036057, Regulation of Proteasome Capacity (3R35GM142728-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11036057. Licensed CC0.

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