# Lens capsule and secondary cataract

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $378,946

## Abstract

PROJECT SUMMARY
Posterior capsular opacification (PCO) is a major vision-impairment problem that emerges after cataract
surgery and Nd:YAG laser posterior capsulotomy is required to restore vision. During PCO, the lens epithelial
cells (LECs) that remain tethered to the anterior capsule after cataract surgery proliferate, migrate to the
posterior capsule where they undergo epithelial-to-mesenchymal transition (EMT) and secrete extracellular
matrix, leading to fibrous tissue formation along with wrinkling of the posterior capsule. Transforming growth
factor-2 (TGFβ2) has been proposed as a major driver of EMT. We have previously demonstrated that the
advanced glycation end products (AGEs) present in aged lens capsules promote the TGFβ2-mediated EMT of
LECs. In our preliminary studies for this proposal, we have discovered that capsule-AGEs through binding to
RAGE receptor promote senescence of LECs. We have also observed that senescent LECs promote EMT of
nonsenescent LECs through paracrine mechanisms. Our data also suggest a greater synthesis of TGFβ2 in
senescent cells than nonsenscent cells. Based on these observations, we propose a novel hypothesis that
capsule AGEs induce senescence in LECs, which promotes the EMT of LECs during posterior capsule
opacification. This hypothesis is further supported by our recent observation of senescent cells in the
posterior capsules of psuedophakic human donor eyes. In Aim 1, we will test the hypothesis that lens capsule
AGEs induce senescence of LECs through formation of reactive oxygen species in cells cultured on AGE-
modified extracellular matrix. In Aim 2, we will test the hypothesis that senescent cells promote the EMT of
human LECs through paracrine mechanisms. The secretion of TGFβ2 and IL-6 from senescent cells and their
ability to induce EMT in nonsenescent cells will be investigated. In Aim 3, we will test the hypothesis that
inhibition/downregulation of RAGE prevents LEC senescence and PCO-like changes in human capsular bags.
Together, the proposed studies are expected to expand our understanding of the molecular mechanisms of
lens fibrosis and aid in the development of novel drugs for treating PCO.

## Key facts

- **NIH application ID:** 10433474
- **Project number:** 1R01EY033915-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Ram H Nagaraj
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,946
- **Award type:** 1
- **Project period:** 2022-09-30 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433474

## Citation

> US National Institutes of Health, RePORTER application 10433474, Lens capsule and secondary cataract (1R01EY033915-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433474. Licensed CC0.

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