# Molecular Basis for Lens Transparency

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $502,334

## Abstract

The long term goals of this research program is to illuminate the mechanistic principles that
describe small heat-shock proteins (sHSP) chaperone activity, reveal the sequence and
structural elements underlying their oligomer dynamics and polydispersity, and define their
physiological roles in the context of the proteostasis network. The focus has been historically on
lens -crystallins which are hypothesized to buffer protein aggregation of damaged lens proteins
in the absence of turnover thereby delaying the onset of cataracts. A thermodynamic model of
the interaction of sHSP with client proteins and an integrated structural biology approach has
long underpinned our research program. With the recent spectacular progress in the genetic
manipulation of zebrafish (D. rerio), this program has transitioned to a new phase of testing
mechanistic models in a living animal. Premised on a detailed mechanistic model and grounded
in discoveries in the previous funding period, this renewal will test two hypotheses describing
the physiological roles of -crystallins. Aims 1 and 2 will use zebrafish lines genetically
engineered with compromised oxidative response, reduced chaperone capacity or expressing
truncated crystallins to experimentally test the long-standing paradigm in the field that -
crsytallins bind and sequester aggregation-prone proteins in vivo. Aim 3 will follow up on our
recent discovery that B-crystallin is critical for survival of zebrafish under stress. The
mechanistic underpinning of this finding is a direct link to glucocorticoid-activated signaling
pathways. Synthetic glucocorticoids administration has been long associated with posterior
subcapsular cataracts. We will investigate how stimulation of the glucocorticoid receptor affects
lens proteostasis. The design of these aims will leverage our protein engineering efforts which
have yielded variants with designed chaperone activity, including phosphorylation mimics of B-
crystallin. In addition to revealing the physiological roles of sHSP, the research plan will have
direct impact on current efforts for therapeutic interventions to delay or treat cataracts. Zebrafish
models generated in the context of this application will provide a valuable tool for high
throughput screening.

## Key facts

- **NIH application ID:** 9997933
- **Project number:** 5R01EY012018-23
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Hassane S Mchaourab
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,334
- **Award type:** 5
- **Project period:** 1998-02-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997933

## Citation

> US National Institutes of Health, RePORTER application 9997933, Molecular Basis for Lens Transparency (5R01EY012018-23). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9997933. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*