# Exploring metabolic governance of immune cell form and function

> **NIH NIH DP2** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $506,488

## Abstract

PROJECT SUMMARY
In this proposal we want to understand the metabolic factors that are essential to tissue-resident
macrophage (TRM) development and function. New advances in metabolomics technology have
helped to decode how cellular metabolism helps to shape immune cell form and function, but
these developments have so far generally stopped short of meaningfully probing the metabolism
of immune cells within the tissues themselves. For cells like TRMs, that exclusively reside within
the tissues, a full understanding the biology of these cells is missing until we can identify how they
utilize cellular metabolism to support their tissue-specific identity and function. Given the important
roles TRMs play in maintaining tissue homeostasis and shaping pathogenic environments, it is
essential we begin to probe the biochemistry of these cells. We present an approach for exploring
TRM metabolism in vivo. Through the use of metabolic tracers in vivo and rapid isolation of TRMs
from the tissue, we detail how this approach will be used to identify metabolic programs essential
to TRM development and function within the tissues. We show how proof of principle testing of
this framework reveals the polyamine-hypusine axis as a novel metabolic node active in
differentiating monocytes and TRMs. We implement in vitro and in vivo validation studies laid out
in our framework, which include bone marrow chimera, parabiosis and novel mouse model
creation, to show that this pathway is essential for the development and maintenance of TRMs
across a multitude of organs. We also propose a highly novel approach to studying TRM
metabolism in humans. Using normathemic perfusion machines, we will perfuse human organs
with metabolic tracers to gain an understanding of human TRM biology in situ. Crucially, we will
employ this approach to experimentally test the pathways identified as important in mouse TRMs
in a human setting. Finally, a major focus of this proposal is to explore TRM metabolism within
tumors. Using similar approaches outlined above for TRMs during homeostasis, we will evaluate
the metabolic activity of TAMs using well defined murine tumor models. We will use our innovative
human system that allows us to experimentally manipulate human organs to probe the
metabolism of human hepatocellular carcinoma lesions and of the TRMs that reside inside them.
Through these orthogonal approaches across species, we expect to build up a detailed picture of
tumor macrophage metabolic activity that can be used to identify novel pathways that can be
targeted to modulate these cells within tumors for therapeutic benefit.

## Key facts

- **NIH application ID:** 10901981
- **Project number:** 5DP2AI177905-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Daniel Puleston
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,488
- **Award type:** 5
- **Project period:** 2023-08-08 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901981

## Citation

> US National Institutes of Health, RePORTER application 10901981, Exploring metabolic governance of immune cell form and function (5DP2AI177905-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10901981. Licensed CC0.

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