# BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $572,100

## Abstract

Brain-derived neurotrophic factor (BDNF) and its associated, specific tropomyosin related kinase B (TrkB)
receptor modulates basal myocardial function and low circulating BDNF levels correlate with worsening of
symptoms in heart failure (HF) subjects. Deleting BDNF in myocytes leads to prominent LV dilation at baseline,
but basal and stress-stimulated left ventricle (LV) function was never tested in cBDNF-/- mice. Our pilot data
suggest that left ventricles from human and experimental HF subjects are massively BDNF depleted. Despite
this experimental and clinical evidence, cardiac BDNF/TrkB remains largely understudied. The long-term goal is
to determine factors accounting for loss in BDNF/TrkB signal in failing hearts, and mechanisms whereby re-
introducing BDNF via TrkB stimulation in BDNF-depleted failing hearts affords protection against ischemic and
non-ischemic stress. Here we advance the following three novel hypotheses: 1) that myocardial BDNF
generation prevents chronic cardiac decompensation in infarcted hearts, and proper βAR activity is involved
in this generation; 2) that direct S1PRs stimulation enhances myocardial BDNF production, preventing LV
decompensation in infarcted mice, and that selective β1AR-blockers rescue β3AR down-regulation in post-MI
hearts, increasing myocardial BDNF levels via β3-AR/S1PRs signal; 3) that cardiac TrkB stimulation rescues
β-AR sensitivity and improves decompensation in a dog model of non-ischemic cardiomyopathy.
The rationale for the proposal is that understanding how loss in BDNF/TrkB signal contributes to myocardial
adaptation to ischemic or non-ischemic cardiac stress will advance efforts to therapeutically harness this capacity
for clinical relevant conditions associated to loss of cardiomyocytes due to ischemic or non-ischemic cardiac
diseases. The central hypotheses will be tested in three integrated Specific Aims. In Aim 1, we will determine
if deleting myocardial BDNF worsens outcome in mice with myocardial infarction, and to test whether TrkB
agonists rescues BDNF expression and β-AR sensitivity in infarcted hearts, the latter by inhibited GRK2, the
major kinase liable for cardiac β-AR desensitization. In Aim 2, we will test if direct β3-AR or S1PRs stimulation
enhances myocardial BDNF content to protect the myocardium against myocardial infarction; In Aim 3, we will
test whether the chronic infusion of TrkB agonists rescues LV function in dogs with tachypacing-induced HF via
improved myocardial efficiency and restored β-AR sensitivity. The proposed research is significant, because
it is expected to foster our understanding of a novel compensatory mechanism, BDNF/TrkB signal that can
enable the heart to preserve functional integrity and energetic efficiency in myocardial cells under condition of
ischemic or non-ischemic stress, and to determine whether TrkB agonists merit further consideration for clinical
testing in HF.

## Key facts

- **NIH application ID:** 10072070
- **Project number:** 5R01HL136918-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Nazareno Paolocci
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $572,100
- **Award type:** 5
- **Project period:** 2018-01-11 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072070

## Citation

> US National Institutes of Health, RePORTER application 10072070, BDNF TrkB- and beta-AR signals in ischemic and non-ischemic cardiomyopathy (5R01HL136918-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10072070. Licensed CC0.

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