# Cellular Signaling Pathways in the Regulation of Fetal Hemoglobin for Treatment of Sickle Cell Disease

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2021 · $168,360

## Abstract

PROJECT SUMMARY/ABSTRACT
 The goal of the proposed five-year training plan is the development of my independent research career as
an academic adult hematology physician-scientist studying red cell biology and hemoglobin regulation. I have
completed internal medicine residency and hematology/oncology fellowship training at the University of
Pennsylvania, and I am currently a Senior Fellow/Program Scholar who will transition in July 2021 to an
Instructor and attending physician in the Division of Hematology/Oncology at UPenn. I am specifically seeking
to develop and refine the skills that will be required for a successful career as an independent investigator,
including expertise in gene regulation, signaling pathways, functional genomics, and bioinformatics. My
overarching goal is to improve therapeutic approaches for sickle cell disease (SCD) via study of key signaling
pathways that regulate expression of the fetal form of hemoglobin. My mentor for this award is Dr. Gerd Blobel,
an internationally recognized leader in erythroid gene regulation and hemoglobin switching. To add depth and
breadth to my scientific and career guidance, I have assembled a Mentoring Committee composed of
physician-scientists from diverse and complementary fields. I will have the full resources of UPenn and the
Children’s Hospital of Philadelphia available for the completion of my research and career development goals.
 The goal of this proposal is to elucidate the molecular mechanisms of PP6C, a novel regulator of fetal
hemoglobin, to improve upon current treatments for SCD and beta-thalassemia. SCD afflicts millions of people
worldwide and can lead to severe complications including acute chest syndrome, stroke, avascular necrosis of
bone, and nephropathy. Although increasing levels of fetal hemoglobin (HbF) significantly reduces cell sickling
and SCD-related morbidity and mortality, effective HbF pharmacologic induction has been an elusive goal. To
this end, I recently carried out a CRISPR-Cas9 based screen to identify additional potentially druggable
molecules to increase HbF production; this screen uncovered the protein phosphatase PP6C as a novel HbF
regulator. This proposal will explore PP6C-regulated pathways with both hypothesis-driven and unbiased
approaches and will investigate suitability of PP6C as a target for HbF induction. These objectives will be
achieved via three Specific Aims: to elucidate key mechanistic pathways in the regulation of HbF by PP6C, to
explore potential cooperativities of PP6C with other HbF regulatory pathways utilizing CRISPR-Cas12a-based
techniques; and to test the role of PP6C-mediated HbF regulation in SCD and in vivo models. The outcome of
these studies will deepen our understanding of signaling pathways that govern HbF expression and unveil new
therapeutic opportunities in SCD. Completion of these aims will consolidate my experience in models of
hemoglobin switching, further my training in bioinformatics and functional genomics, ...

## Key facts

- **NIH application ID:** 10282012
- **Project number:** 1K08DK129716-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Scott Alan Peslak
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $168,360
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10282012

## Citation

> US National Institutes of Health, RePORTER application 10282012, Cellular Signaling Pathways in the Regulation of Fetal Hemoglobin for Treatment of Sickle Cell Disease (1K08DK129716-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10282012. Licensed CC0.

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