# Cap-Dependency in Hematopoietic Stem and Progenitor Cell Translation

> **NIH NIH F31** · HARVARD MEDICAL SCHOOL · 2021 · $39,551

## Abstract

Project Abstract
Hematopoietic stem and progenitor cells (HSPCs) produce blood and immune cells throughout the lifespan of
an organism and must be preserved, especially to survive and function under stresses like infection,
inflammation, and bone marrow transplantation. While extensive research has elucidated transcriptional
programs and niche factors that maintain HSPCs, few studies have explored post-transcriptional mechanisms,
which are critical for rapid stress responses. Translation regulation allows cells to quickly shift translational output
in response to stimuli, including stressors and growth cues, by targeting single or groups of mRNAs based on
unique or shared translation regulatory motifs. Stem cells are known to have characteristically low rates of total
protein synthesis in comparison to differentiated cells; however, few studies have further characterized subtypes
of translational regulatory motif activity in HSPCs. My goal is to understand how HSCPs differentially employ
mechanisms of translational regulation in steady state and stress. I am particularly interested in regulation of the
rate-limiting step of translation: initiation. Most mRNAs require a collection of eukaryotic initiation factors to
assemble at the 5’ cap of an mRNA to recruit ribosomes. Terminal oligopyrimidine (TOP) motifs are one example
of translation regulatory motifs regulated in this cap-dependent manner; TOPs are pyrimidine-rich sequences
that exist in the 5’ UTRs of many growth-associated genes. Alternatively, some mRNAs bypass the need to
assemble some or all eukaryotic initiation factors at the 5’ cap and are classified as cap-independent transcripts.
Internal ribosome entry sites (IRESs) are one example of a translation regulatory motif regulated in a cap-
independent manner. IRESs have been identified in mammalian 5’ UTRs to regulate the translation of genes
important for cell survival and differentiation; their unique 5’ UTR secondary structures allow ribosome complexes
to load onto mRNAs without some or all of the cap-machinery, especially under stress conditions. In this project,
I will compare cap-dependent (TOP) and cap-independent (IRES) translation regulatory motif activity across
hematopoiesis in steady state and stress to understand their role in HSPC function and survival. In my first aim,
I will create vectors that compare several IRES- and TOP-translation motifs and compare rates of cap-dependent
and cap-independent translation across hematopoiesis in steady state. Since translation regulation is particularly
relevant to the cellular stress response, my second aim will assess translational changes across hematopoiesis
in response to stresses like bacterial infection, chemotherapy, and bone marrow transplantation by assessing
reporter activity and performing ribosome-immunoprecipitations to determine changes in the translatome. In my
third aim, I will determine if cap-dependent and cap-independent translation rates predict HSPC regeneration...

## Key facts

- **NIH application ID:** 10228305
- **Project number:** 1F31HL158020-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Michael Mazzola
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $39,551
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10228305

## Citation

> US National Institutes of Health, RePORTER application 10228305, Cap-Dependency in Hematopoietic Stem and Progenitor Cell Translation (1F31HL158020-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10228305. Licensed CC0.

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