# Polyploidy after tissue injury: a Drosophila model

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $319,700

## Abstract

Metazoan tissues are diverse in organization and function. This necessitates diverse mechanisms to
repair these tissues upon injury. We pioneered study of the Drosophila hindgut (large intestine) to reveal new
tissue injury regulation. Using this model, we identified an injury response whereby tissue mass is restored by
increasing the DNA content (ploidy) and size of cells that survive injury. This increase in ploidy involves a
conserved cell cycle with S phases but no cell division, called the endocycle. Our discovery of endocycles and
polyploid cells in tissue repair has been followed by similar discoveries in multiple injured mammalian tissues,
including the kidney, bladder, and cornea. Additionally, our work revealed specialized polyploid cell regulation at
the injured boundary between the hindgut and adjacent midgut (small intestine). At this boundary, we identified
“hybrid” cells of dual hindgut and midgut gene expression. Hybrid cells become polyploid upon injury while
engaging in extensive cross-talk with stem cells in the adjacent midgut. However, if the hybrid zone is severely
injured, polyploidy is suppressed, and the adjacent midgut stem cells form hyperplastic invasive tumors. Similar
hybrid zones have now been discovered at mammalian organ boundaries, notably at the stem cell-enriched,
cancer-prone stomach/esophagus boundary.
 This proposal leverages our expertise, new findings, and the genetically amenable Drosophila model to
identify regulation and function of polyploidy after tissue injury. The significance of our proposed work is evident
in the conservation of the injury response, the conservation of endocycles in injury, and the conservation of the
molecules we study, including JAK/STAT signaling, Dichaete/SoxB1, and fizzy-related/cdh1. Our studies are
innovative because they show that tissues can regenerate by accurately controlling polyploid genome number,
that hormonal signaling and Sox transcription cooperate to control injury-induced polyploidy, and that a
regenerating polyploid organ boundary can suppress tumorigenesis. In Aim1, we will uncover how injury severity
determines the extent of polyploidy during regeneration. To answer this question, we will identify quantitative
parameters of JAK/STAT signaling at different injury strengths and identify specific pathway steps that coordinate
injury level with endocycle number. Aim2 will identify the molecular mechanism by which endocycles occur after
injury instead of mitosis. To answer this question, we will examine how Dichaete, a member of the conserved
Sox transcription factor family, cooperates with hormone signaling to promote a switch from injury-induced mitotic
cycles to endocycles. Aim3 will determine the origin and function of polyploid hybrid cells following injury. To
answer this question, we will distinguish between stem cell-dependent and stem cell-independent models of
organ boundary regeneration. Additionally, this aim will reveal the role of the hybrid zone an...

## Key facts

- **NIH application ID:** 10756503
- **Project number:** 5R01GM118447-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Donald T. Fox
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $319,700
- **Award type:** 5
- **Project period:** 2016-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10756503

## Citation

> US National Institutes of Health, RePORTER application 10756503, Polyploidy after tissue injury: a Drosophila model (5R01GM118447-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10756503. Licensed CC0.

---

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