# A Holistic Approach to Understanding Small Heat Shock Protein Mechanism

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $406,301

## Abstract

ABSTRACT/SUMMARY
Cells have numerous strategies to cope with the consequences of stresses that cause protein
misfolding and aggregation and lead to formation of plaques, fibrils, and other aggregated
species encountered in aging cells, cataract, and neurodegenerative diseases. The protein
chaperones known as small heat shock proteins are the cell’s first responders and are therefore
key to maintenance of cellular health. Ocular tissues are subjected to stresses such as
exposure to UV light, smoking, hypoxia, and ischemia. sHSP function is linked to three of the
most prevalent ocular pathologies leading to blindness worldwide: cataract, age-related macular
degeneration, and diabetic retinopathy which together account for 65% of world blindness. In
lens, sHSPs perform the critical task of maintaining lens transparency and failure to do so is
directly linked to cataract. sHSPs are expressed constitutively in retinal cells and are
upregulated following injury or stress. Mechanisms used by sHSPs to delay the onset of
aggregation of proteins remain enigmatic due to technical challenges posed by sHSPs and the
aggregate-prone proteins they protect. Recent developments in the study of disordered proteins
and breakthroughs made during the previous period of this long-standing project promise to
overcome this critical barrier to mechanistic understanding. Techniques such as NMR,
hydrogen-deuterium exchange/mass spectrometry, and covalent cross-linking/mass
spectrometry can provide fine-grained information regarding disordered regions of sHSPs that
have largely gone uncharacterized but are known to be essential for sHSP activity. The goal of
this renewal application is to develop a holistic (“characterized by comprehension of the parts of
something as intimately interconnected and explicable only by reference to the whole”)
understanding of sHSP structure and function. The effects of stress conditions, modifications,
and mutations will be assessed and interpreted in the context of the resultant novel models.

## Key facts

- **NIH application ID:** 10848187
- **Project number:** 5R01EY017370-16
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Rachel E Klevit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $406,301
- **Award type:** 5
- **Project period:** 2007-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848187

## Citation

> US National Institutes of Health, RePORTER application 10848187, A Holistic Approach to Understanding Small Heat Shock Protein Mechanism (5R01EY017370-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10848187. Licensed CC0.

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