# Replication Stress and Ribosome Biogenesis in Hematopoietic Stem Cell Aging

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $46,036

## Abstract

PROJECT SUMMARY/ABSTRACT
 Diseases of the elderly are an increasingly urgent societal problem due to the worldwide increases in
lifespan. The aging of the hematopoietic system is caused by dysfunction in hematopoietic stem cells (HSC) and
is characterized by anemia, thrombocytosis, and overproduction of myeloid cells at the expense of
lymphopoiesis. Together these defects play a key role in the development of cardiovascular diseases, loss of
adaptive immunity that impedes vaccination, and establishment of chronic systemic inflammation that damages
tissue and contributes to frailty. HSC aging is conserved in mammals, with human and murine old HSCs (oHSC)
both exhibiting reduced regenerative potential, genomic instability, epigenetic drift, metabolic rewiring, and
altered cell-cell communication. Although these overt phenotypic features are widely understood to be significant
characteristics of oHSCs, we still know little about their underlying molecular mechanisms and functional
consequences. This gap in knowledge has hindered efforts to delay or reverse HSC aging at its root. Our lab
identified replication stress as a potent driver of oHSC dysfunction and impaired regenerative potential. This is
especially severe at fragile ribosomal DNA loci, leading to loss of ribosome biogenesis. This project aims to
determine the functional consequences of reduced ribosome biogenesis for oHSCs, and to identify the programs
that underly replication stress initiation with a goal to target them to restore oHSC function. Our preliminary
data suggest that oHSCs are defective in their capacity for protein translation, even though their mitogenic
signaling pathways are overactive. They also suggest chronic activation of the Nucleolar Stress Response (NSR)
as a consequence of replication stress in oHSCs. Furthermore, we have evidence for epigenetic alterations and
cell cycle transcriptional repression consistent with Mcm downregulation and replication stress initiation. In Aim
1, we will determine the extent of defective protein translation in quiescent and activated oHSCs using in vitro
and in vivo approaches. We will also interrogate the signaling pathways driving defective protein translation in
oHSCs focusing in particular on NSR activation using a mouse genetic approach. These experiments will
establish how defective proteostasis contribute to HSC aging, and the connection between replication and
nucleolar stress in driving oHSC impaired regeneration potential. In Aim 2, we will identify the transcription
factors or cell cycle regulators responsible for replication stress initiation, and also uncover the epigenetic basis
for this defect. We will then assess whether pharmocological tuning of specific epigenetic modifiers can restore
oHSC function. These experiments will dissect the molecular underpinnings of replication stress and determine
whether correcting this cell-intrinsic hallmark of HSC aging will improve oHSC regenerative potential. Altogether,
our propo...

## Key facts

- **NIH application ID:** 10314933
- **Project number:** 1F31HL160207-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Carl Mitchell
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314933

## Citation

> US National Institutes of Health, RePORTER application 10314933, Replication Stress and Ribosome Biogenesis in Hematopoietic Stem Cell Aging (1F31HL160207-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10314933. Licensed CC0.

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