# Novel Humanized Mouse Models For Engraftment of Tissue-Specific Human Macrophage Population

> **NIH NIH R24** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $881,450

## Abstract

Tissue resident macrophages are derived from embryonic yolk sac progenitors, develop prior to birth, are long-
lived and radioresistant, and have critical functions in maintaining tissue homeostasis and in the pathogenesis
of many human diseases that are of broad interest to NIH. This proposal is to build cutting-edge humanized
mouse resources that support the efficient development of human tissue resident macrophages in disease
relevant models and is in response to RFA-22-013: “Resource-Related Research Projects for Development of
Animal Models and Related Materials”. The rationale for our approach is based on the paucity of translational
animal models that are readily available to the research community to study human tissue resident
macrophages in vivo and evaluate their role in human diseases. While several humanized platforms
expressing human cytokines have been reported to improve development of human macrophage populations,
many of these models are not available to basic research programs. Moreover, these models are often focused
on engraftment of single macrophage populations and thus lack components of the adaptive immune system
and other innate immune cells. An additional limitation for humanized models is that the mouse resident
macrophage populations occupy the “niches” available for tissue specific macrophages and resist replacement
with human HSC-derived macrophages. We recently knocked out the fms-intronic regulatory element (FIRE)
enhancer in the CSF1 receptor gene in immunodeficient NSG mice (NSG-Fire) that impairs the development of
mouse tissue resident macrophages, and we are crossing NSG-(Fire) mice with cytokine transgenic NSG mice
to promote the development of human myeloid cells. Our overall hypothesis is that genetic modification of NSG
mice to express species-specific, myeloid promoting cytokines and to reduce mouse tissue resident
macrophage populations will enhance the development of functional human tissue resident macrophages and
provide a robust small animal model for the study of inflammatory immune responses mediated by human
macrophage populations. We will test this hypothesis in three Specific Aims. Aim 1) Generation of novel NSG-
(Fire) mouse stocks that are deficient in mouse tissue resident macrophages and express human cytokines for
development of human myeloid cells. Aim 2) Engraftment of novel NSG-(Fire) mouse stocks with CD34+ UCB-
HSC and evaluation of human tissue resident macrophage development. Aim 3) Testing NSG-(Fire) strains as
a model for tissue resident macrophages acting as a reservoir for HIV during latency and for microglia in
Alzheimer’s Disease-relevant neurodegeneration. These new mouse models will allow for the in vivo
investigation of human tissue resident macrophages in multiple diseases and accelerate the development of
human specific therapies.

## Key facts

- **NIH application ID:** 10849269
- **Project number:** 1R24OD036199-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Michael Allen Brehm
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $881,450
- **Award type:** 1
- **Project period:** 2024-07-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10849269

## Citation

> US National Institutes of Health, RePORTER application 10849269, Novel Humanized Mouse Models For Engraftment of Tissue-Specific Human Macrophage Population (1R24OD036199-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10849269. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*