# Genetic dissection of angiogenesis in the tuberculous granuloma

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $397,500

## Abstract

Abstract
Mycobacterium tuberculosis kills approximately 1.5 million people annually. It has long
been observed that mycobacterial granulomas can be extensively vascularized, but the
functional consequences of this vascularization have not been fully examined. Using a
zebrafish mycobacterial infection model that recapitulates important aspects of human
mycobacterial granulomas, we found that granuloma-induced angiogenesis coincides
with the generation of local hypoxia and transcriptional induction of the canonical pro-
angiogenic molecule Vegfa. Interception of this pathway with clinically used inhibitors
resulted in reduced burden and improved outcome. Building on our preliminary data that
suggest a role for the VEGF pathway and the bacterial lipid trehalose dimycolate, we will
define the cellular and molecular mechanisms by which pathogenic mycobacteria
promote the pro-angiogenic environment of mycobacterial granulomas to facilitate their
own growth, dissemination and survival. We also will probe the role of a parallel
canonical angiogenic signaling pathway – the angiopoietin/Tie2 pathway – for which we
have identified a novel host-directed drug that we have shown to be effective in reducing
mycobacterial burden in zebrafish. Finally, we will build on our recent data showing
induction of these pathways in human granuloma specimens and probe the functional
effects of human genetic variants in mycobacterial infection. Overall, this proposal tests
the hypothesis that, in a striking parallel to tumor biology, the interplay of angiogenesis,
hypoxia and compromised vasculature contributes to mycobacterial pathogenesis.
Ultimately, the modulation of these pathways may provide new strategies for host-
directed therapies for tuberculosis.

## Key facts

- **NIH application ID:** 9851786
- **Project number:** 5R01AI125517-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** David M. Tobin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,500
- **Award type:** 5
- **Project period:** 2017-02-15 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851786

## Citation

> US National Institutes of Health, RePORTER application 9851786, Genetic dissection of angiogenesis in the tuberculous granuloma (5R01AI125517-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851786. Licensed CC0.

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