# Identifying new regulators of cardiac fibrosis and inflammation using zebrafish

> **NIH NIH R01** · BOSTON COLLEGE · 2024 · $391,250

## Abstract

Project Summary/Abstract
 Several cardiac diseases involve the progressive or acute loss of cardiomyocytes, which are replaced by
fibrotic tissue. Cardiac fibrosis is one of the leading factors in the pathology of heart failure, a progressive disease
that affects millions of people every year. Despite its recognized importance, there are no effective therapies to
prevent the progression of cardiac fibrosis. Recent findings suggest that naturally occurring genetic variants
protect certain individuals against the adverse changes triggered after cardiac injury, which translates into re-
duced cardiac fibrosis. One of the genes that modifies the progression of disease is the cardiomyocyte-specific
kinase Tnni3k. Mutations that abolish Tnni3k confer resistance to injury, and high Tnni3k levels are associated
with rapid functional decline and pathological remodeling. Tnni3k is an understudied kinase, and its downstream
targets and specific mechanisms by which it defines injury outcome are unknown. Our goal in this project is to
identify the mechanisms linking Tnni3k levels to cardiac fibrosis. In preliminary experiments using the zebrafish
as a model, we found that high levels of Tnni3k induce fibrosis deposition shortly after cardiac injury. In contrast
to their wild-type siblings, animals overexpressing Tnni3k showed impaired fibrotic regression, while a newly
generated tnni3k mutant exhibits minimal fibrosis after injury. Transcriptional profiling revealed that high levels
of Tnni3k correlate with an exacerbated inflammatory response, markers of T-cell infiltration, and activation of
all the components of the inflammasome, which are all landmarks of cardiomyocyte-induced inflammation. We
also identified a potential downstream target, itih5, which has been previously reported to play a role in extracel-
lular matrix stabilization in the skin. Based on our preliminary results, our central hypothesis is that Tnni3k
plays a previously unappreciated role in cardiac fibrosis via modulation of inflammation, and that Itih5 is a central
mediator of these effects. We will test our hypothesis in three integrative aims. In Aim 1, we will determine the
role of inflammation in the development of fibrosis in response to high levels of Tnni3k. We will exploit a collection
of immunocompromised zebrafish to test the contribution of specific immune populations to this excessive fibrotic
response. Additionally, we will use a new cardiomyocyte specific Cas9 line to identify genes required for trigger-
ing inflammation in response to high Tnni3k levels. In Aim 2, we will determine the effects of modulating Tnni3k
levels pre- and post-injury on cardiac fibrosis and inflammation. We will use a new Tnni3kSWITCH line generated
by our lab that will allow us to “turn off” the overexpression of Tnni3k at different times. In Aim 3, we will identify
molecular regulators of scar remodeling downstream of Tnni3k. We will start by analyzing how Itih5 regulates
fibrosis regression usi...

## Key facts

- **NIH application ID:** 10912073
- **Project number:** 5R01HL164749-03
- **Recipient organization:** BOSTON COLLEGE
- **Principal Investigator:** Juan Manuel Gonzalez-Rosa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2023-08-22 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912073

## Citation

> US National Institutes of Health, RePORTER application 10912073, Identifying new regulators of cardiac fibrosis and inflammation using zebrafish (5R01HL164749-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10912073. Licensed CC0.

---

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