# Functions, mechanisms, and therapeutic potential of fetal hemoglobin inducers

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $652,900

## Abstract

Abstract
Sickle cell disease (SCD) and some types of b-thalassemia that are caused by defects in
the adult form of hemoglobin manifest shortly after birth, when the switch from the fetal
to the adult form of hemoglobin is complete. Even a partial reversal of this switch is
associated with an improved course of these diseases. We employed a newly improved
CRISPR-Cas9 platform to carry out a kinase domain-focused genetic screen to identify
potentially druggable molecules that repress fetal hemoglobin (HbF) production. This
screen uncovered HRI (also known as EIF2AK1), an erythroid-specific protein kinase
that regulates protein translation. Depletion of HRI elevates HbF levels in human
erythroid cells with few additional perturbations. HRI loss reduces the expression of the
major HbF repressor BCL11A, and restoration of BCL11A expression partially restores
HbF repression. Moreover, HRI depletion reduces sickling of SCD-derived human
erythroid cells in culture. In Aim 1 we will comprehensively dissect HRI function by
assessing the transcriptome and proteome of HRI-depleted cells. The goals of Aim 2 are
to study the mechanism by which HRI regulates BCL11A, identify additional HRI
regulated HbF repressors, and examine the global impact of HRI on protein translational
control in primary human erythroid cells. Aim 3 will explore synergies with previously
known HbF inducers both using a candidate approach, and by unbiased genetic screens
for novel synergies. In Aim 4 we will examine the effects of HRI loss on SCD by
generating HRI-deficient humanized SCD mouse models. In sum, these studies explore
the role of HRI in human red cell biology and examine HRI as target for pharmacologic
HbF induction alone or in combination with mechanistically distinct HbF inducers.

## Key facts

- **NIH application ID:** 9843507
- **Project number:** 5R01HL119479-07
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Gerd A Blobel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $652,900
- **Award type:** 5
- **Project period:** 2013-08-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843507

## Citation

> US National Institutes of Health, RePORTER application 9843507, Functions, mechanisms, and therapeutic potential of fetal hemoglobin inducers (5R01HL119479-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9843507. Licensed CC0.

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