# Investigation into the role of autophagy protease ATG4A in normal and impaired erythropoiesis

> **NIH NIH K01** · UNIVERSITY OF WASHINGTON · 2024 · $148,014

## Abstract

PROJECT SUMMARY/ ABSTRACT
Autophagy is a self-degradation pathway that has tissue-specific functions in erythropoiesis. During erythroid
differentiation, autophagy facilitates the degradation of macromolecules and the programmed clearance of
mitochondria. The long-term objective of this proposal is to determine how autophagy contributes to normal and
impaired erythropoiesis. Patients with Myelodysplastic syndromes (MDS) often have impaired erythropoiesis
and mitochondrial dysfunction. A subset of MDS, MDS with ring sideroblasts (RS), contain the aberrant
accumulation of iron-laden mitochondria in erythroblasts suggesting that autophagy may be dysregulated in
hematopoietic disorders and impair erythroid differentiation. While essential autophagy genes are known to
contribute to autophagy in erythropoiesis, little is known about the tissue-specific regulation of autophagy during
human erythroid differentiation. We have identified the selective expression of the autophagy protease ATG4A
in the erythroid lineage. We have evaluated the contribution of ATG4A in an ex vivo model of human erythroid
differentiation. Early in differentiation, ATG4A promotes the expansion and colony formation of erythroid
progenitors. Late in differentiation, ATG4A promotes terminal maturation, enucleation, and mitochondrial
clearance. Since ATG4 proteases are regulated by reactive oxygen species, the function of ATG4A in
erythropoiesis may be sensitive to oxidative stress. Based on our preliminary results, we hypothesize that
ATG4A mediates autophagy during early and late erythropoiesis and is dysregulated by oxidative stress. In aim
1, we will identify the role of ATG4A-dependent autophagy in early erythropoiesis. In aim 2, we will determine
the mechanism of ATG4A-dependent mitochondrial clearance. In aim 3, we will examine the regulation of
mitochondrial clearance in human models of MDS-RS. The experiments outlined in this proposal will be
conducted under the mentorship of Dr. Sergei Doulatov, an expert in the development and use of human iPSC
models to study erythroid disorders, and co-mentorship of Dr. Janis Abkowitz, Chair of the Division of
Hematology at the University of Washington and international expert in MDS and erythroid biology. This career
development award will support my training to become an independent investigator studying the contribution of
autophagy to normal and dysfunctional erythropoiesis.

## Key facts

- **NIH application ID:** 10770406
- **Project number:** 5K01DK128126-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Massiel Chavez Stolla
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $148,014
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770406

## Citation

> US National Institutes of Health, RePORTER application 10770406, Investigation into the role of autophagy protease ATG4A in normal and impaired erythropoiesis (5K01DK128126-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10770406. Licensed CC0.

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