# Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $410,000

## Abstract

PROJECT SUMMARY
Healthy adults produce 2 million erythrocytes every second through the process of basal erythropoiesis.
Insufficient erythrocyte production causes anemia, which is a significant global human health problem. During
regeneration or “stress erythropoiesis” to recover from anemia, erythrocyte production further increases. Stress
erythropoiesis is critical for recovery from surgery, chemotherapy, bone marrow transplantation and infection;
however, the underlying mechanisms remain unclear. Both basal and stress erythropoiesis are regulated by
erythropoietin (Epo) and its receptor EpoR. Epo binding to the EpoR activates the associated tyrosine kinase
JAK2, which initiate downstream signaling leading to survival, proliferation and differentiation of erythroid cells.
While EpoR signaling in more differentiated erythroid precursors has been extensively studied, EpoR signaling
in early progenitors has not been elucidated.
This proposal is based on our recent findings of a previously unrecognized population of early colony-forming
erythroid progenitors (CFU-E), which we named stress CFU-E or sCFU-E. sCFU-E are targets of Epo, are only
expanded in erythroid stress, and are essential for recovery of the erythron. sCFU-E are also hijacked by the
activating JAK2 mutant, JAK2(V617F), to drive erythrocytosis in myeloproliferative neoplasms. In preliminary
studies, we discovered that sCFU-E proliferation and differentiation involve novel Epo/EpoR signaling. We
found that Epo induces expression of Nocturnin, a NADP(H) phosphatase that regulates cellular oxidative
stress to promote sCFU-E proliferation. Epo also induces expression of SLC23A2, an ascorbate (Vitamin C)
transporter, in sCFU-E. sCFU-E accumulates high levels of ascorbate, and ascorbate accelerates sCFU-E
differentiation. The goal of this proposal is to elucidate the mechanism by which Nocturnin and ascorbate drive
proliferation and differentiation of sCFU-E in the context of stress erythropoiesis and erythrocytosis. Aim 1 will
determine the role of ascorbate import on sCFU-E function. Aim 2 will elucidate mechanisms underlying
ascorbate-dependent sCFU-E differentiation. Aim 3 will determine the role of Nocturnin and oxidative stress
signaling in sCFU-E proliferation. These results will elucidate mechanisms controlling stress erythropoiesis and
erythrocytosis, and may lead to novel therapeutic interventions for anemia and those that can target
erythrocytosis while preserving basal erythropoiesis.

## Key facts

- **NIH application ID:** 10824360
- **Project number:** 5R01HL089966-16
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** LILY JUNSHEN HUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2007-09-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10824360

## Citation

> US National Institutes of Health, RePORTER application 10824360, Erythropoietin receptor signaling in stress erythropoiesis and erythrocytosis (5R01HL089966-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10824360. Licensed CC0.

---

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