# Metabolic Control of Erythroid Differentiation

> **NIH NIH R01** · PENNSYLVANIA STATE UNIVERSITY, THE · 2020 · $305,003

## Abstract

Project summary: Anemia is a significant human health problem that is caused by multiple etiologies and has
negative impact on quality of life. Standard treatments for anemia are transfusion therapy and treatment with
erythropoiesis stimulating agents, which can be effective in the short-term, but are not without risk. Treatment
of chronic anemia with transfusion therapy is complicated by the risk of allo-immunization and the potential for
infection. While, erythropoiesis stimulating agents are not effective treatments for all anemia and their
immunomodulatory properties can compromise other treatments. These observations point to a need in the
field to identify new treatments for anemia. One possibility is to characterize the physiological response to
anemic stress. Previous work in my lab showed that in response to hypoxic stress, bone marrow steady state
erythropoiesis is unable to maintain homeostasis. At these times, stress erythropoiesis predominates. Stress
erythropoiesis is best understood in the murine system where it is extra-medullary, occurring in the adult
spleen and liver and in the fetal liver during development. Stress erythropoiesis utilizes a different strategy than
steady state erythropoiesis. Instead of generating new erythrocytes at a constant rate, stress erythropoiesis
generates a bolus of new erythrocytes designed to alleviate anemia until steady state erythropoiesis can
resume. This strategy relies on the ability of immature stress erythroid progenitors to proliferate without
differentiating. The expansion of this transient amplifying population is an essential step in stress
erythropoiesis. If too few early progenitors are generated or if they differentiate prematurely, insufficient
erythrocytes will be produced to alleviate the anemia. In this proposal submitted under the SHINE II program
announcement, we will focus on the mechanisms that regulate the expansion of early stress progenitors and
the mechanisms that inhibit their differentiation during this expansion phase. We hypothesize that stress
erythroid progenitors adopt a pro-inflammatory metabolism characterized by increased glucose and glutamine
metabolism, which results in the production of anabolic intermediates needed to produce lipids, nucleotides
and amino acids necessary for cell proliferation. In addition, this metabolic program produces metabolites that
promote the activity of histone methylases that maintain repression of the erythroid differentiation program.
This model demonstrates how metabolic regulation can coordinate the proliferation and differentiation of stress
erythroid progenitors during the recovery from anemic stress.

## Key facts

- **NIH application ID:** 9885429
- **Project number:** 1R01HL146528-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** ROBERT Frank PAULSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $305,003
- **Award type:** 1
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9885429

## Citation

> US National Institutes of Health, RePORTER application 9885429, Metabolic Control of Erythroid Differentiation (1R01HL146528-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9885429. Licensed CC0.

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