# Mechanisms of Hydroxyurea Efficacy in Sickle Cell Disease

> **NIH NIH K01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $140,700

## Abstract

PROJECT SUMMARY
Sickle cell disease (SCD) is one of the most commonly inherited blood disorders world-wide with an annual
cost of over 1 billion dollars in the United States alone. Currently, there is only one FDA-approved drug for
managing SCD, hydroxyurea (HU). HU efficacy is attributed largely to augmented expression of gamma-globin
in erythroid progenitors leading to increased production of fetal hemoglobin to ameliorate many complications
of SCD. However, the increase in fetal hemoglobin may not be sufficient for some patients, and they may not
benefit this therapy for reasons that are unknown. With limited alternative therapies available there is a need to
improve efficacy of HU and develop new drugs for these patients. This project will provide new information
about the mechanisms of HU efficacy that can offer pharmacogenetic targets to help personalize HU therapy
and offer new therapeutic targets of fetal hemoglobin induction for developing additional treatments for SCD.
Its novel concepts combined with a detailed training plan and mentorship from a highly accomplished team of
translational and clinical researchers will also facilitate the career development of the principle investigator.
Our previous work investigating modulators of HU pharmacology has identified that the cell membrane
transporters urea transporter B (UTB) and organic cation/carnitine transporter1 (OCTN1) regulate the
intracellular accumulation of HU. These transporters govern how much drug reaches intracellular targets and
are associated with augmented fetal hemoglobin levels. We also found that intracellular miRNAs, miR- 148a, -
151-3p, and -494 are associated with HU therapy in erythroid cells of sickle cell patients in association with
increased fetal hemoglobin level. Thus, we have identified two potential mechanisms through which HU may
elicit an increase in fetal hemoglobin levels. To date, model limitations have hindered our studies to investigate
these modulators in an in vivo model of SCD. Given these previous findings, we hypothesize that induction of
fetal hemoglobin by hydroxyurea is modulated by transporters and miRNAs. In the rich research environment
at University of Pittsburgh, using an in vitro model of erythropoiesis, we will test our hypothesis in the following
two aims: 1) to determine whether UTB and OCTN1 transporters control uptake and efficacy of HU to induce
fetal hemoglobin and 2) to determine whether miR-148a, -151-3p, and -494 control the efficacy HU to induce
fetal hemoglobin. In a third aim, we will develop a novel in vivo model to dissect these and other mechanisms
of hydroxyurea-mediated fetal hemoglobin in SCD.
While conducting the translational research, the candidate will also take classes, participate in career
development programs, learn technical skills in viral gene transduction and improve professional competencies
related to communication, mentoring, teaching, management and leadership. Throughout the project mentoring
by a team ...

## Key facts

- **NIH application ID:** 9983149
- **Project number:** 5K01HL133518-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Aisha Lanette Walker
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $140,700
- **Award type:** 5
- **Project period:** 2017-08-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983149

## Citation

> US National Institutes of Health, RePORTER application 9983149, Mechanisms of Hydroxyurea Efficacy in Sickle Cell Disease (5K01HL133518-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983149. Licensed CC0.

---

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