# A novel immunometabolism-regulatory axis in inflammatory hematopoiesis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $385,896

## Abstract

PROJECT SUMMARY/ABSTRACT
 The emerging field of immunometabolism has its basis in that inflammation is a hallmark of many chronic
metabolic disorders. Central to the link between the immune and metabolic systems is the mitochondrion, which
has been recognized as the major player in the orchestration of inflammatory pathways and immune cell function.
While much attention on immunometabolic regulation has been given to conventional mature immune cells,
recent few scattered studies on the relationship between metabolism and hematopoietic stem cells (HSCs) raise
a completely different perspective on the immunological/metabolic interface between HSC defects and human
diseases. How immunometabolism influences HSC function, and what signaling cascades help drive cell-intrinsic
immunometabolic modes in HSCs, has begun to emerge as an area of intense interest.
 We have employed Fanconi anemia (FA), a genetic bone marrow failure syndrome known to impact the
immune system, deregulate mitochondrial metabolism and promote inflammation, to study immunometabolic
regulation in hematopoietic stem and progenitor cells (HSPCs). We and others have demonstrated that
inflammation in FA HSPCs plays a crucial role in FA pathophysiology. Recently, we have shown that FA HSCs
are more dependent on mitochondrial respiration relative to glycolysis in their resting state for energy
metabolism. However, the mechanism underpinning the link between inflammation and the altered metabolic
program in FA HSCs has not been defined. More recently, we exploited the well-established repopulating defect
of FA HSCs to conduct an unbiased in vivo shRNA screen followed by global gene profiling and functional
studies, and identified a deregulated FA/Hes1/Ppar/FAO signaling axis as a potential missing link between
inflammation and dysfunctional metabolism in the context of FA HSC defect. These preliminary studies suggest
that the FA pathway may constitute a key component of a novel immunometabolism axis connecting
inflammation, cellular metabolism and HSC function. We hypothesize that the FA pathway regulates HSC
immunometabolism involving a pathway hierarchy in which the FA core signals to Fancd2, which then acts in
concert with the transcriptional repressor Hes1 to suppress Pparg expression and consequently FAO in HSC
maintenance. To test this, we will first determine whether the FA pathway regulates Pparg expression through
Hes1 and assess the requirement for the co-repression of Pparg expression by the FA pathway and Hes1 in the
regulation of FAO in inflammation-stressed HSCs. We will then investigate the functional link between
dysregulated immunometabolism and inflammation-associated HSC defects.

## Key facts

- **NIH application ID:** 10369047
- **Project number:** 5R01HL151390-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Wei Du
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $385,896
- **Award type:** 5
- **Project period:** 2020-12-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369047

## Citation

> US National Institutes of Health, RePORTER application 10369047, A novel immunometabolism-regulatory axis in inflammatory hematopoiesis (5R01HL151390-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10369047. Licensed CC0.

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