# Elucidation of cellular reprogramming processes that drive lens regeneration in axolotl as a basis for future therapeutic approaches

> **NIH NIH R00** · UNIVERSITY OF NEW HAMPSHIRE · 2024 · $247,715

## Abstract

Salamanders, like newts and axolotls, can regenerate ocular tissues when injured. This is possible due to 
the ability of their pigmented epithelial cells to reprogram to retina and lens. The goal of this research is to 
unravel the reprogramming mechanism and leverage it for regenerative medicine applications. The main 
focus of the study is the ability of iris pigmented epithelial (IPE) cells to get activated, proliferate, 
reprogram, and ultimately regenerate the lens upon its complete removal. In newts, this process is 
restricted to IPE cells residing in the dorsal iris while ventral IPE cells are thought to not participate at the 
cellular level. In contrast, juvenile axolotls cannot regenerate their lens. These regenerative discrepancies 
enable the use of experimental paradigms that could provide important insights into the molecular 
mechanism of IPE reprogramming. In Specific Aim 1, a combination of comparative transcriptomics, flow 
cytometry sorting and lineage tracing will be used to identify and characterize IPE subpopulations capable 
of triggering a regenerative response. These approaches will also be paired with a novel transgenic newt 
capable of tracking changes in eye transcriptional factor dynamics during reprogramming. This will allow us 
to better understand the association between molecular and cellular changes during regeneration. In 
Specific Aim 2, functional characterization of lens regeneration will be performed. To successfully 
accomplish that, the avian RCAS/TVA system will be implemented to provide spatial and temporal control 
of target gene expression in the pigmented epithelium. The avian TVA receptor will be ubiquitously 
expressed in eye tissues, in dorsal IPE cells, or in ventral IPE cells making them susceptible to the RCAS 
retrovirus. Using this system, the effects of genes and pathways will be tested for their ability to induce 
regeneration from the ventral, or inhibit regeneration from the dorsal IPE cells, respectively. This approach 
provides a functional readout by performing necessity and sufficiency experiments. In Specific Aim 3, the 
relationship between aging, DNA damage, and regeneration potential will be explored. Newts can 
regenerate their lens from IPE cells throughout life and the ability appears unaffected by aging and 
repeated injury. First, a repeated injury model will be developed and coupled with molecular hallmarks of 
aging and DNA damage. Then, pharmacological and genetic methods will be used to study the effects of 
elevated genotoxic stress on the ability of the pigmented epithelium to reprogram to eye tissues.

## Key facts

- **NIH application ID:** 10758580
- **Project number:** 5R00EY029361-04
- **Recipient organization:** UNIVERSITY OF NEW HAMPSHIRE
- **Principal Investigator:** Konstantinos Sousounis
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $247,715
- **Award type:** 5
- **Project period:** 2019-05-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10758580

## Citation

> US National Institutes of Health, RePORTER application 10758580, Elucidation of cellular reprogramming processes that drive lens regeneration in axolotl as a basis for future therapeutic approaches (5R00EY029361-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10758580. Licensed CC0.

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