# Normal and Pathological Hematopoietic Stem Cells in Obesity

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $397,500

## Abstract

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PROJECT DESCRIPTION
Obesity is a chronic organismal stress that impacts multiple biological functions and tissues. Obesity and its
sequelae modulate the immune system and the hematopoietic activity in the bone marrow (BM). Notably,
obesity has been associated with altered immunological functions and an overall increased risk for
hematological malignancies. However, despite their clinical relevance, the mechanisms by which obesity
affects the health of the hematopoietic system and might contribute to its pathological dysregulation have yet to
be characterized. Here, we seek to decipher the impact of obesity on the molecular and cellular fitness of the
hematopoietic stem cell (HSC) compartment. In Aim1, we will investigate the cell-intrinsic molecular
mechanisms that allow HSCs to cope with the aberrant environmental stresses triggered by obesity. Based on
our preliminary results, we will focus on the transcriptional factor Gfi1 as we found that up-regulation of this
factor is crucial in regulating HSC fate in obesity. Notably, we uncovered a novel molecular circuit that links
oxidative stress and Gfi1 expression in HSCs. Here we will determine the molecular mechanisms underlying
this link in obesity. We will also test the hypothesis that Gfi1 up-regulation affects the long-term fitness of the
HSCs by modulating their ability to mount proper stress responses. In Aim2, we will investigate at the single
cell level how obesity disrupts the homeostasis of the HSC compartment. We will determine whether the obese
environment alters the molecular and functional, clonal diversity of the HSC compartment, leading to the
development of a clonal hematopoiesis. Finally, we will test the hypothesis that the obese environment could
favor the emergence of clones carrying pre-neoplastic features. Altogether, our studies will elucidate the
impact of obesity on the hematological system. They will test the hypothesis that obesity alters the HSC
intrinsic regulatory programs, affects the clonal structure of the HSC pool and promotes the emergence of pre-
leukemic HSC clones. These studies stand to make critical contributions to our understanding of the adverse
effects of chronic obesity on the health of the HSC compartment. In the midst of a global obesity epidemic, the
long-term goal of this project is to decipher the potential risks associated with the use of obese donors for BM
stem cell transplantation and the influence of obesity on the long-term development of pre-neoplastic
hematopoiesis.

## Key facts

- **NIH application ID:** 10134814
- **Project number:** 5R01HL141418-04
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Damien Reynaud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134814

## Citation

> US National Institutes of Health, RePORTER application 10134814, Normal and Pathological Hematopoietic Stem Cells in Obesity (5R01HL141418-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134814. Licensed CC0.

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