# Genetic Mechanisms of Tissue-Resident Macrophage Maintenance and Function (Supplement)

> **NIH NIH R35** · MICHIGAN STATE UNIVERSITY · 2024 · $86,272

## Abstract

Summary
Macrophages are critical components of the innate immune system that sample the local environment, respond
to stimuli and return tissues to homeostasis. Distinct macrophage populations play unique roles in these
processes. Macrophages derived from circulating monocytes are rapidly recruited to infections, are
inflammatory, and are generally short-lived. In contrast, long-lived tissue resident macrophages (TRMs) are
derived from fetal liver cells and play an important role in maintaining homeostasis in the absence of infections.
While monocyte-derived macrophages are well defined, due to experimental limitations there remain many
open questions regarding how TRMs are maintained and contribute to regulating the local environment. To
address these key gaps in knowledge my research group is developing new ex vivo models of distinct TRM
populations that can then be probed using functional genetics. We recently developed an ex vivo model for
lung-specific TRMs, alveolar macrophages (AMs), that maintain expression of AM-specific markers and
function. Using this model we engineered a genome-wide knockout library in AM-like cells that enables rapid
forward genetic screens using our customized screening pipeline. Over the next five years my research group
will leverage this innovative resource to dissect underlying biological mechanisms related to AM maintenance
and function. We will comprehensively define the genes required to maintain cells in the AM-like state using a
combination of iterative genetic screens with in-depth functional characterization. These experiments will
uncover entirely novel signaling and transcriptional networks activated in AMs during homeostasis. In parallel,
we will compare the genetic control of core macrophage functions between myeloid-derived macrophages
(BMDMs) and AM-like cells. While there are metabolic and transcriptional differences between BMDMs and
AMs, it remains entirely unknown how these differences alter genetic control of macrophage functions like
phagocytosis. We will complete screens in both BMDMs and AM-like cells probing phagocytosis of distinct
cargo. These datasets will define shared and unique pathways that control core macrophage functions and will
illuminate new mechanisms of fundamental biological processes. Finally, my research group will lay the
groundwork for dissecting genetic pathways in AMs in intact animals by optimizing a cell transfer and
screening pipeline. Using this model, we will uncover the in vivo role of key AM genes and identify new
pathways required for AMs to maintain lung homeostasis. Accomplishing these goals will position my research
group to understand the underlying mechanisms controlling AMs in detail not previously possible. Our long-
term goal is to expand these approaches and findings to more broadly understand other TRM populations by
identifying shared mechanisms of function and maintenance.

## Key facts

- **NIH application ID:** 11021401
- **Project number:** 3R35GM146795-03S1
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Andrew Olive
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $86,272
- **Award type:** 3
- **Project period:** 2022-06-23 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11021401

## Citation

> US National Institutes of Health, RePORTER application 11021401, Genetic Mechanisms of Tissue-Resident Macrophage Maintenance and Function (Supplement) (3R35GM146795-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11021401. Licensed CC0.

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