# Protein quality control in age-related diseases

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $486,909

## Abstract

ABSTRACT
Protein quality control is vital for cellular function, encompassing pathways that help proteins fold and maintain structural
conformations, as well as cellular systems that ultimately degrade proteins. Several degenerative diseases, including those
that are accompanied by abnormal aging, are associated with altered protein quality control, highlighting the importance
of protein fidelity in both health and disease. CHIP (carboxyl terminus of heat shock 70-interacting protein) is a multi-
functional enzyme with distinct activities that contribute both to protein folding and protein degradation. Our lab recently
identified the first human disease associated with CHIP mutations, with phenotypes that include accelerated aging,
cerebellar ataxia and degeneration, cognitive dysfunction, and hypogonadism. Two known CHIP substrates, receptor-
interacting protein kinase 3 (RIPK3) and AMP-activated kinase (AMPK), are regulated by either the degradative or re-
folding activities of CHIP, respectively. These kinases regulate important cellular processes, necroptosis (an inflammatory
form of programmed cell death) and cellular metabolism, both of which are central to the ability of cells to react to the
stress that occurs with aging or in pathophysiological conditions. In this proposal, we seek to define the role of protein
quality control in aging by determining how the various activities of CHIP regulate these recently identified
substrates, and the mechanism that drives the sensitivity to cell stress when CHIP function is compromised. Our
approach includes novel pre-clinical models of accelerated aging, cutting-edge cell models, and determining the molecular
movements of CHIP when engaged with its substrate. We then ask how disease-causing mutations in CHIP
mechanistically drive the molecular and cellular phenotypes associated with CHIP dysfunction. Finally, we will use our
preclinical models to determine how aging and disease pathologies are altered when necroptosis is inhibited
pharmacologically, or when CHIP function is restored genetically. The ultimate goal of these studies is to identify
druggable targets of CHIP-regulated signaling pathways that impact age-dependent progression of degenerative
conditions.

## Key facts

- **NIH application ID:** 9944769
- **Project number:** 1R01AG066710-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Jonathan C. Schisler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $486,909
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944769

## Citation

> US National Institutes of Health, RePORTER application 9944769, Protein quality control in age-related diseases (1R01AG066710-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944769. Licensed CC0.

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