# Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $593,584

## Abstract

Project Summary
Coronary heart disease is the leading cause of death in the U.S., and patients who survive a coronary artery
occlusion have a high risk for cardiac arrhythmias and sudden cardiac death. Spatial heterogeneity of
sympathetic transmission is a major contributor to post-infarct arrhythmias and sudden cardiac death after
myocardial infarction (MI), and sympathetic denervation predicts arrhythmia risk in human studies. During the
previous period of support we discovered that persistent denervation was caused by chondroitin sulfate
proteoglycans (CSPGs) in the scar acting on neuronal Protein Tyrosine Phosphatase Receptor Sigma (PTPσ).
Targeting PTPσ using genetics or the therapeutic peptide ISP promoted reinnervation. Deletion of PTPσ
normalized myocyte β-AR signaling, cardiac electrophysiology, and myocyte Ca2+ handling, rendering hearts
resistant to isoproterenol-induced arrhythmias. We hypothesize that it is reinnervation, not the lack of PTPσ,
which normalizes cardiac electrophysiology and Ca2+ handling after MI. We will test that hypothesis using two
therapeutics to restore cardiac nerves: ISP which targets PTPσ, and a novel small molecule (HJ-2) which binds
TrkA. This will allow us to distinguish the effects of reinnervation, which is stimulated by both drugs, from other
drug-specific effects. We will determine if reinnervation normalizes cardiac electrophysiology and Ca2+
handling, if reinnervation and its effects are sustained, and if noradrenergic transmission is required for
restoring electrical stability in the heart. We will determine if sympathetic reinnervation during scar maturation
enhances cardiac repair or alters the inflammatory response, and if delayed reinnervation is protective. We
have assembled an outstanding team of experts along with novel chemical reagents and imaging tools to
assist us in completing these studies. This work will test if stimulating nerve regeneration with therapeutics can
normalize cardiac electrophysiology and decrease arrhythmias, and will identify the mechanisms involved.

## Key facts

- **NIH application ID:** 10439477
- **Project number:** 5R01HL093056-13
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** BETH A HABECKER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $593,584
- **Award type:** 5
- **Project period:** 2009-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439477

## Citation

> US National Institutes of Health, RePORTER application 10439477, Neurotrophins and post-infarct plasticity in cardiac sympathetic neurons (5R01HL093056-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439477. Licensed CC0.

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