# Targeting the Calcitonin-BMP1 Pathway in Atrial Cardiofibroblasts to Ameliorate Atrial Fibrillation

> **NIH NIH F30** · BAYLOR COLLEGE OF MEDICINE · 2024 · $52,037

## Abstract

One of the most prevalent diseases is atrial fibrillation (AF), which contributes to at least 180,000 deaths annually
and is expected to affect twelve million people in the U.S. by 2030. Excessive atrial fibrosis increases resistance
to therapy and decreases AF-free survival in AF patients by creating a substrate for atrial reentrant arrhythmias.
Increased interstitial fibrosis is caused by dysfunctional atrial cardio-fibroblasts (ACFs) that secrete excessive
collagen into the extracellular matrix. However, detailed molecular mechanisms of the signaling pathways
regulating ACFs are yet to be uncovered, which could enable the development of a novel treatment for AF. The
Wehrens Lab in collaboration with Dr. Reilly (Univ. of Oxford) has recently identified calcitonin (CT) as a paracrine
signaling molecule that is released from cardiomyocytes and suppresses atrial fibrosis. The study showed that
CT overexpression ameliorates AF progression in a novel murine model of spontaneous AF. Moreover, it found
that treating human cultured ACFs with CT inhibited BMP1 cleavage activity and reduced collagen deposition.
BMP1 is a zinc-dependent protease that cleaves and activates several profibrotic substrates, including the TGF-
β large latent complex (LLC) to release secreted TGF-β, a profibrotic signal protein. However, the roles of BMP1
that are regulated by CT have yet to determined. While the previous study suggests that CT treatment
ameliorates AF development in mice, it also found that ACFs from AF patients are resistant to CT treatment
because the CT receptor (CTR) is downregulated as AF progresses. The hypothesis is that a reduction in CT
receptor activation on ACFs leads to enhancement of BMP1 activity, more TGF-β LLC cleavage, and thus more
atrial fibrosis and AF progression. To test this hypothesis, Aim 1 will determine whether BMP1 activity mediates
the regulation of TGF-β by CT in human ACFs, and Aim 2 will determine whether Bmp1 knockout protects against
the development of atrial fibrosis and AF in mice. These studies will provide a more detailed understanding of
the signaling pathway downstream of CT in atrial fibrosis and AF and offer a candidate for a novel gene therapy
approach to reduce atrial fibrosis for the treatment of AF. To accomplish these goals, the proposed training plan
includes learning the relevant research skills such as optical mapping, telemetry ECG recording and analysis,
and histology for analyzing fibrosis. An additional aspect of the training plan involves shadowing cardiologists
throughout the Texas Medical Center as they care for patients with AF and other arrhythmias and practicing
clinical skills during graduate school at the San José Clinic. The research environment is likewise well suited to
the project and training goals and includes dedicated lab spaces for molecular biology studies, mouse
electrophysiology and telemetry recording, mouse surgery, and optical mapping as well as a mentor and
postdoctoral associates wh...

## Key facts

- **NIH application ID:** 11076176
- **Project number:** 5F30HL167574-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Kevin Son Ho
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $52,037
- **Award type:** 5
- **Project period:** 2023-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11076176

## Citation

> US National Institutes of Health, RePORTER application 11076176, Targeting the Calcitonin-BMP1 Pathway in Atrial Cardiofibroblasts to Ameliorate Atrial Fibrillation (5F30HL167574-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11076176. Licensed CC0.

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