# Regulation of metabolism by the Aryl hydrocarbon receptor in hematopoietic and immune cell progenitors

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN MILWAUKEE · 2022 · $225,048

## Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and global environmental
sensor responsive to exogenous and endogenous microenvironmental ligands that we propose plays a central
role coordinating the metabolic state of hematopoietic stem and progenitor cells. The choice made by
hematopoietic stem cells between remaining quiescent and undergoing self-renewal, versus proliferating and
differentiating into a lineage-restricted progenitor cell, is based on the balance of signals that promote catabolic
versus anabolic metabolic activities. Catabolism is defined by recycling of organelles and proteins for self-
renewal and quiescence, whereas anabolic production of energy and nutrients drives proliferation and
differentiation. Hence, the fundamental question that will drive this and subsequent studies is what is the
physiological role for the AHR on the balance of catabolic versus anabolic metabolism during hematopoiesis?
The Long-term goal of our team is to uncover the mechanisms by which the AHR tunes the cellular metabolic
state during the transition from hematopoietic stem cell to effector immune cell in response to
microenvironmental stimuli. In pursuit of our goal, the objective of this high risk – high reward R21 proposal is to
identify the role for the AHR on global regulation of mitochondria in hematopoietic stem and lineage-biased
progenitor cells. The overarching hypothesis is that the AHR is a central regulator of metabolism in hematopoietic
and immune system progenitors. The scientific premise that the AHR is a central regulator of metabolism is
grounded, in part, on our exciting preliminary data that show: (1) the number of mitochondria in hematopoietic
stem cells is specifically regulated by the AHR; and (2) the AHR is required for maximal oxidative burst in
hematopoietic progenitors. The three specific aims employed to interrogate the overarching hypothesis are: Aim
1: Determine the AHR signaling thresholds required for mitochondria biogenesis during hematopoiesis. Aim 2:
Identify the contribution of AHR-dependent signaling on anabolic activity of hematopoietic progenitors. Aim 3:
Establish the AHR-dependent signaling thresholds required for maintaining catabolic activities in hematopoietic
stem cells. This proposal is significant because it will for the first time identify a physiological role for the AHR in
the balance of catabolic vs anabolic activities, thereby regulating metabolism of HSC and lineage-biased immune
cell progenitors. This proposal is highly innovative as it represents a substantive departure from the status quo
by linking the mechanism of hematopoietic regulation by the AHR to the metabolic drivers of quiescence,
proliferation and differentiation. An expected outcome from these studies will be real-time visualization of
mitochondria homeostasis dependent on AHR activity in hematopoietic stem and progenitor cells. The positive
impact of the proposed work will be new avenues for treatment...

## Key facts

- **NIH application ID:** 10353238
- **Project number:** 1R21ES033748-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN MILWAUKEE
- **Principal Investigator:** Michael D Laiosa
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $225,048
- **Award type:** 1
- **Project period:** 2021-12-10 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353238

## Citation

> US National Institutes of Health, RePORTER application 10353238, Regulation of metabolism by the Aryl hydrocarbon receptor in hematopoietic and immune cell progenitors (1R21ES033748-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10353238. Licensed CC0.

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