# Regulation of hemoglobin production in normal and disease states

> **NIH NIH K08** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $159,828

## Abstract

PROJECT SUMMARY / ABSTRACT
 Reversing the developmental switch from fetal (HbF) to adult hemoglobin is an important therapeutic
approach in sickle cell disease (SCD). HbF expression in healthy adults, patients with SCD, or those treated with
pharmacologic HbF inducers is distributed heterogeneously in a subset of cells called “F-cells”; increasing the
number of F-cells as well as the HbF content in each F-cell are both important for treatment of SCD. I have
developed techniques for purification and characterization of primary human F-cells and their comparison to
equivalent A-cells, which do not express HbF. My preliminary data show that the two cell types differ primarily in
their globin content but not in expression of any known HbF regulators, and that F-cells have increased long-
range chromatin contacts between the locus control region (LCR) enhancer and the promoters of the g-globin
genes. My preliminary studies and the experiments proposed in this proposal represent the first attempt to
characterize F-cells by direct comparison to A-cells. I propose to further characterize F-cells from healthy adults,
patients with SCD, and following treatment with three pharmacologic HbF inducers using cutting-edge
techniques for studies of transcriptional bursting kinetics, chromatin accessibility and long-range chromatin
interactions. In addition, I will explore the function of three chromatin remodeling enzymes identified in a loss of
function genetic screen for modulators of HbF expression. My proposed studies will further our understanding of
the mechanisms of HbF regulation and heterogeneity of HbF expression in clinically important contexts and will
guide the development of more effective therapeutics for sickle cell disease.
 This proposal describes a five-year training plan for the development of my independent research career as
an academic pediatric hematologist physician-scientist studying red cell biology and hemoglobin regulation. I am
an Instructor in Pediatrics at the University of Pennsylvania and an attending physician in the Division of
Hematology at the Children’s Hospital of Philadelphia (CHOP) with previous PhD training in cell and molecular
biology and red blood cell biology. The goals for this award are to develop and refine the essential skills that will
be required for a successful career as an independent investigator, including expertise in gene regulation,
epigenetics, and bioinformatics. My mentor for this award is Dr. Gerd Blobel, an internationally recognized leader
in epigenetics, erythroid gene regulation, and developmental control of hemoglobin switching. I have also
enlisted an advisory committee composed of scientists and physician-scientists with complimentary expertise
and mentoring experience, and have the full resources of CHOP and the University of Pennsylvania available
for the completion of my research and career development goals. Completion of this proposal in a mentored
environment will leave me optimally pos...

## Key facts

- **NIH application ID:** 10189076
- **Project number:** 1K08DK128571-01
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Eugene Khandros
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $159,828
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189076

## Citation

> US National Institutes of Health, RePORTER application 10189076, Regulation of hemoglobin production in normal and disease states (1K08DK128571-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10189076. Licensed CC0.

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