# Animal Model Core E

> **NIH NIH U19** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $156,346

## Abstract

Core E. Animal Model Core
Project Leader: Clare Smith
ABSTRACT
Understanding the mechanisms through which Mycobacterium tuberculosis (Mtb) metabolites impact human
tuberculosis (TB) disease requires implementation of model animal systems that are both tractable and
faithfully replicate the TB disease states observed in humans. Here we propose to leverage the Collaborative
Cross (CC), a genetically diverse panel of recombinant inbred mice that can be reproducibly and indefinitely
regenerated. We have previously shown that the CC panel encompasses a broad spectrum of TB disease
traits and infection microenvironments. CC mice provide a tractable model in which to study specific Mtb
genetic-metabolite pairs, compared to standard inbred mice that show limited phenotypic variability. For
example, in a genome-wide TnSeq experiment, we found that among 19 high value Mtb metabolic genes, only
one controlled growth in the conventional C57BL/6J (BL6) mouse strain. However, more than half of mutants
studied showed in vivo growth phenotypes when screened across CC mouse strains. Further, through study of
the host genetic backgrounds in which individual bacterial genes do or do not control in vivo Mtb survival, the
Smith laboratory can begin to study host factors in control of Mtb response. The Animal Core E will conduct
experimental infection approaches to support Projects 1 and 3 that focus on virulence associated lipids and
diagnostics, respectively. To support identification of Mtb metabolites as diagnostic tests in Project 3, we will
characterize lungs and serum from mice infected with a high and low burden of Mtb. Supporting efforts to
understand the role of host pressure on the mycobacterial envelope content in Project 1, we will produce Mtb
strains passaged in vivo in mice. Extending our existing Tnseq approach to identify mycobacterial genes that
control Mtb growth in vivo, we will select and test up 50 pooled Mtb CRISPR knockdown strains for pulmonary
infection in CC strains. From these, five Mtb CRISPR knockdown strains with the strongest in vivo growth
phenotypes will be further studied in detail as single gene knockdowns to determine their specific functions.

## Key facts

- **NIH application ID:** 10271483
- **Project number:** 1U19AI162584-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Clare Margaret Smith
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $156,346
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271483

## Citation

> US National Institutes of Health, RePORTER application 10271483, Animal Model Core E (1U19AI162584-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10271483. Licensed CC0.

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