# Mechanisms of Polyploidy and Aneuploidy in the Liver

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $469,947

## Abstract

PROJECT SUMMARY / ABSTRACT
Liver disorders affect 30 million people in the United States and are the 10th leading cause of death in the US.
Nearly 40,000 patients will develop end-stage liver disease, resulting in 30,000 annual deaths. Liver
transplantation is the most effective therapy but is severely limited by donor organ supply, thus necessitating
the development of therapeutic alternatives to whole organ replacement. A better understanding of hepatocyte
biology is required to improve existing approaches and innovate therapies for liver disease treatment.
Hepatocytes display a range of chromosomal diversity, resulting from prevalent physiological polyploidy and
aneuploidy. Most eukaryotic cells contain a diploid genome comprised of homologous chromosome pairs.
Polyploidy refers to gains in entire chromosome sets, and aneuploidy refers to gains and/or losses of individual
chromosomes. The underappreciated role of hepatic polyploidy and aneuploidy represents a major gap in our
current understanding of liver biology. Recently, it was observed that diploid hepatocytes proliferate faster than
polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the
majority of hepatocytes. Together with earlier work suggesting aneuploid hepatocytes protect in chronic liver
injury, the data indicate that hepatic chromosomal diversity represents a novel form of liver heterogeneity. The
central hypothesis tested is the following: Hepatocytes with altered chromosome content (diploid vs. polyploid;
aneuploid vs. euploid) have context-dependent functions that optimize liver regeneration and response to
acute/chronic liver injury. Aim 1 will characterize the role of diploid and polyploid hepatocytes during
acetaminophen (APAP)-induced acute liver injury. Experiments will test whether diploid hepatocytes promote
healing by enhanced compensatory liver regeneration, and they will identify mechanisms that regulate
accelerated cell cycling. Aim 2 will determine whether disrupted tissue architecture promotes chromosome
segregation errors and aneuploidy by proliferating hepatocytes. Experiments using a novel cell polarity
deficiency model will test whether polarity disruptions promote hepatic chromosome segregation errors and
aneuploidy. Moreover, it will be determined whether defective polarity by transplanted hepatocytes can drive
this process. Aim 3 will determine whether human hepatic aneuploidy is a selectable mechanism for cell
adaptation. Experiments will test if hepatocytes with advantageous aneuploidy accelerate liver repopulation
and determine whether increased background aneuploidy accelerates adaptation to chronic injury. Both
beneficial and pathological effects of aneuploidy will be determined. Overall, the research strategy will reveal
new functions for hepatocytes with chromosome heterogeneity and uncover mechanisms that regulate their
activity, which will provide new and crucial insights into liver homeost...

## Key facts

- **NIH application ID:** 10129950
- **Project number:** 5R01DK103645-07
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ANDREW W DUNCAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $469,947
- **Award type:** 5
- **Project period:** 2014-09-25 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129950

## Citation

> US National Institutes of Health, RePORTER application 10129950, Mechanisms of Polyploidy and Aneuploidy in the Liver (5R01DK103645-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129950. Licensed CC0.

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