# Macrophage Reprogramming During Granuloma Formation in the Zebrafish

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $478,644

## Abstract

Abstract
Granulomas form as a conserved host response to a variety of inflammatory and infectious stimuli. As
granulomas assemble, macrophages interdigitate and undergo a striking morphological transition, taking on an
epithelioid appearance. The basis for this transformation and the consequences to disease are not well
understood. We identified a conserved reprogramming of macrophages that underlies the assembly and
stability of mycobacterial granulomas. Using a zebrafish model, we find that broad epithelial modules and
structures are induced during tuberculous granuloma formation and are critical for granuloma integrity. In this
project we will 1) assess how specific Type 2 immune signals interact with countervailing Type 1 signals to
coordinate epithelioid transformation and granuloma assembly; 2) test the role of the EMP2/Focal Adhesion
Kinase (FAK) pathway in granuloma stability, disaggregation and the dissemination of infection; 3) based on
scRNA-seq analysis of granulomas as well as macrophages isolated from individual animals, assess the role
of JAG1-Notch in granuloma formation, maintenance, and infection trajectory. We will extend findings from
these studies into analysis of human disease. Overall, this proposal will test the hypothesis that, in a striking
parallel to mesenchymal-to-epithelial transitions in development and cancer, macrophages draw on classical
developmental signaling pathways to undergo an epithelial-like transition. This reprogramming underlies the
central structure of tuberculosis and defines interactions with the host immune system. We will test how
perturbations of these pathways lead to alterations in disease progression and outcome. A new perspective on
this critical structure may have important implications for our understanding of disease progression and
provides opportunities for new therapeutic approaches.

## Key facts

- **NIH application ID:** 10772010
- **Project number:** 5R01AI130236-08
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** David M. Tobin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $478,644
- **Award type:** 5
- **Project period:** 2017-03-03 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772010

## Citation

> US National Institutes of Health, RePORTER application 10772010, Macrophage Reprogramming During Granuloma Formation in the Zebrafish (5R01AI130236-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10772010. Licensed CC0.

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