# Elucidating the Role of Death Receptor 5 in the Heart

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2022 · $383,826

## Abstract

Heart failure is a leading cause of morbidity and mortality worldwide. Cardiomyocyte survival and death play a
crucial role in the pathogenesis of heart failure due to the limited capacity of cardiomyocytes to proliferate or
repair. Recently, multiple clinical studies have identified TNF-related apoptosis inducing ligand (TRAIL) and its
receptor, death receptor 5 (DR5), as being two of the most powerful predictive markers of heart failure
development and severity. Additionally, whole transcriptome analysis from our laboratory identified TRAIL and
DR5 alterations in a mouse model of heart failure and its involvement in cardioprotective, EGFR-dependent
signaling. While there have been multiple studies demonstrating high expression of TRAIL and DR5 in the
heart, their function has never been investigated. The role of TRAIL/DR5 in cancer has been extensively
studied due to the ability of TRAIL to selective induce apoptosis in cancer cells, however, in non-transformed
cell types, the function of TRAIL/DR5 is unclear. Due to the connection of TRAIL/ DR5 with heart failure and
unidentified role of TRAIL/DR5 in the heart we have been exploring the impact of DR5 signaling in
cardiomyocytes. Using pharmacological agonists of DR5, we observe that DR5 activation does not induce
canonical death receptor signaling pathways in cardiomyocytes but activates the pro-growth and survival
kinase ERK1/2. Using specific inhibitors for signal transduction pathways, we observe that ERK1/2 activation
involves the transactivation of EGFR and results in cardiomyocyte hypertrophy. Therefore, we hypothesize that
DR5 activation in cardiomyocytes plays a non-canonical, cardioprotective role through the activation of pro-
growth and survival mechanisms. Completion of the following research proposal will contribute important
information to this novel field of study through the identification of the function and signaling mechanisms
initiated by DR5 activation in cardiomyocytes, the role of DR5 in the normal and failing heart and the
determination of the potential of targeting TRAIL/DR5 as a therapeutic strategy in heart failure.

## Key facts

- **NIH application ID:** 10456151
- **Project number:** 5R01HL148080-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Laurel Ann Grisanti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,826
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10456151

## Citation

> US National Institutes of Health, RePORTER application 10456151, Elucidating the Role of Death Receptor 5 in the Heart (5R01HL148080-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10456151. Licensed CC0.

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