# Modeling thoracic aortic aneurysm in zebrafish

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

Project Summary
Thoracic aortic aneurysms (TAAs), occurring at the aortic root, are cardinal features of Marfan Syndrome
(MFS) and Loeys-Dietz Syndrome (LDS) that significantly shorten the lifespans of affected individuals because
they dissect and rupture. Causative mutations for MFS and LDS have implicated perturbed TGFβ signaling in
TAA pathogenesis. However, considerable uncertainty and controversy abound regarding whether high and/or
low TGFβ signaling drives aneurysm formation. Also unclear is whether the nearly universal increases in TGFβ
effector phosphorylation (i.e. pSmad2/3 and pErk1/2), observed in advanced disease, are a primary cause or
secondary consequence of aortic distention. Lastly, the cellular mechanism by which perturbed TGFβ signaling
might promote aneurysm remains undefined. Unfortunately, a small molecule that showed promise in treating
aneurysm in MFS mice recently failed in a clinical trial.
 We have isolated and begun characterizing a novel genetic model of TAA in zebrafish. Animals
deficient in Latent-TGFβ binding proteins (Ltbps) 1 and 3 (ltbp1-/-; ltbp3-/-), molecules that sequester TGFβ
ligands in the extra cellular matrix (ECM), rapidly develop impressive aneurysm of the cardiac outflow tract
(OFT), a structure homologous to the aortic root in mammals, over a two-day period following grossly
unperturbed OFT morphogenesis. We present preliminary data documenting several similarities between
zebrafish and mammalian aneurysm. The shared features include: 1) greater than 50% increases in aortic
diameter; 2) significantly increased phosphorylation of Smad2/3 and Erk1/2 in the aneurysm wall, indicative of
high canonical and non-canonical TGFβ signaling, respectively; 3) disorganization of smooth muscle cells
which contain prominent stress fibers; 4) a propensity to dissect and/or rupture; and 5) overlapping molecular
signatures revealed through a bioinformatics comparison of our recently-acquired RNA-sequencing dataset
with a published microarray dataset from MFS mice. Interestingly, we have discovered elevated expression of
markers for highly differentiated “contractile” smooth muscle in the OFTs of mutant zebrafish prior to any
visible evidence of aneurysm. To my knowledge, few laboratories have investigated gene expression changes
in the aortic root prior to aneurysm emergence in mouse models of MFS and LDS. Therefore, this aspect of the
phenotype is highly novel. I propose several innovative and hypothesis-driven experimental approaches
designed to provide impactful mechanistic insights into TAA pathogenesis. The knowledge obtained will inform
ongoing debates over disease mechanisms and bolster efforts to identify novel therapeutic modalities for
preventing and treating aneurysmal disease. I propose two Specific Aims: 1) to test the hypothesis that
elevated TGFβ signaling is necessary and sufficient to cause aortic aneurysm in zebrafish; and 2) to test the
hypothesis that aberrant phenotypic modulation of smooth musc...

## Key facts

- **NIH application ID:** 9996768
- **Project number:** 5R01HL139806-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** C. Geoffrey Burns
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996768

## Citation

> US National Institutes of Health, RePORTER application 9996768, Modeling thoracic aortic aneurysm in zebrafish (5R01HL139806-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996768. Licensed CC0.

---

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