# Alzheimer's-focused Administrative Supplement to R01EY023219

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $319,258

## Abstract

Project Summary/Abstract
Lens crystallin aggregation and precipitation is the primary cause for cataract formation. A cataract occurs
when the lens α-crystallin ceases to perform its chaperone function of aiding in maintaining lens transparency.
During the course of studies performed on lens crystallin chaperone function, discovered were specific
sequences in αA- and αB-crystallin responsible for the chaperone function. In addition, a deletion mutant of
αB-crystallin (B∆54-61) with a ~10-fold increase in chaperone function during in vitro protein aggregation
assays were developed, suggesting that this recombinant crystallin can be considered a “super chaperone.”
Protein misfolding and aggregation is the primary cause of Alzheimer's disease (AD), Parkinson's disease,
Huntington's disease, Creutzfeldt-Jakob disease, and many other degenerative and neurodegenerative
disorders. Based on the studies conducted with unfolding model substrates, the preliminary data included in
this supplementary request show the “αB∆54-61 super chaperone” developed can alleviate A-induced
paralysis and extend the lifespan in AD model of C. elegans (CL4176) expressing A-peptide. With
supplement award support, it is proposed to test the efficacy of “super chaperones” in protecting
neural cells and C. elegans from β-amyloid (and α-synuclein) aggregation-induced toxicity. Previously
shown, crystallin peptide chaperone that encapsulates the chaperone site in αA-crystallin and a cell penetrable
form of the same (with superior chaperone activity compared to the original mini-chaperone) suppresses β-
amyloid fibril formation and toxicity in vitro. The “super chaperones” also protect ARPE-19 and Cos-7 cells from
oxidative stress-induced apoptosis. Our studies suggest that the “super chaperones” developed could be used
as therapeutics against diseases involving protein aggregation, oxidative stress, and apoptosis. It is proposed
to carry out a systematic study to test the efficacy of peptide chaperones to suppress amyloid
aggregation and toxicity using in vitro experiments, cell culture systems (ARPE-19 cells, N-27 cells and
primary neuronal cells) and in AD model of C. elegans (CL4176). Thus, studies carried out with
supplementary funds to the parent grant will help to develop crystallin based proteins/mini-chaperones that
have therapeutic value. The study will open new avenues for treating AD and related dementias. The long-term
goals of our studies are to develop α-crystallin-based protein and peptide chaperones having therapeutic
value. A supplementary award to the current project, R01 EY023219 - Metastable crystallins- Structure and
Stabilization, will help to expand the study currently focused on protein aggregation diseases of the eye, to
protein misfolding diseases of the brain and other tissues, which share a common etiology to the protein
misfolding diseases of the eye. Once the beneficial effects of the “super chaperones” in the proposed systems
are demonstrated, a p...

## Key facts

- **NIH application ID:** 10122296
- **Project number:** 3R01EY023219-08S1
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** KRISHNA K SHARMA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $319,258
- **Award type:** 3
- **Project period:** 2013-05-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122296

## Citation

> US National Institutes of Health, RePORTER application 10122296, Alzheimer's-focused Administrative Supplement to R01EY023219 (3R01EY023219-08S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10122296. Licensed CC0.

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