# Adrenergic and GRK regulation of exosomes for cardiac regeneration

> **NIH NIH P01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $453,944

## Abstract

Project 2 (Koch)
SUMMARY/ABSTRACT
Cardiac regeneration offers great promise for repair of injured myocardium and heart failure (HF), however it
is not yet reality. This is due to cells not truly regenerating the heart as replacement myocytes. However,
some benefit appears to occur in the post-ischemic heart with different stem cell injections, and data supports
paracrine effects. Recent advances have suggested that the paracrine effects for any improvement in heart
function after stem cell delivery is due to secreted exosomes from these cells. Exosomes are small vesicles
containing specific cargo and it appears that they can carry potentially therapeutic molecules including growth
factors and microRNAs (miRs). Data from our lab over the last two decades has implicated G protein-coupled
receptor (GPCR) kinases (GRKs), especially GRK2, as key molecules in HF development following cardiac
injury. Further, GRK2, which is up-regulated in failing human hearts, has emerged as a potential novel
therapeutic target in HF. GRK2 has important effects on cardiac -adrenergic receptor (AR) signaling that
has crucial implications in HF. Importantly, inhibition of GRK2 with a peptide inhibitor (ARKct) or knock-down
of its expression leads to significant prevention and rescue of animal models of HF and preliminary data
presented in this proposal shows that mechanisms of this repair includes increased markers of myocyte
regeneration. Thus, we are interested in whether GRK2 or AR manipulation in myocytes or cardiac precursor
cells (CPCs) may affect reparative or regenerative properties of the injured heart including examining
paracrine, autocrine or exosome-based properties. We have started to investigate whether manipulation of
GRK2 activity might alter exosomes and their cargo from either myocytes or CPCs, and whether exosomes
from CPCs have improved regenerative properties. Indeed, we have recently found that introduction of the
ARKct into CPCs improves survival and metabolism of these cells. ARKct-containing CPCs, as mediators
of cardiac regeneration, will be employed to investigate whether manipulation of AR signaling and GRK2 activity
may influence exosome-mediated cardiac repair in vivo. We will use mouse models and also move to the pig in
order to carry out pre-clinical studies with the goal of future clinical translation. Specifically, the Central
Hypothesis of this proposal is that inhibition or lowering of GRK2 in cardiac stem/precursor cells and/or cardiac
myocytes improves myocardial repair through mechanisms that include favorable alterations of the content of
secreted exosomes. This may include direct enhancement of -adrenergic signaling that improves survival and
proliferation of these cells to positively affect cardiac regeneration. Specific Aims are: [1] To characterize the
content of exosomes secreted from CPCs and myocytes with altered GRK2 expression and activity that can lead
to changes in AR signaling, and to determine if altered exos...

## Key facts

- **NIH application ID:** 9980470
- **Project number:** 5P01HL134608-04
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Walter J. Koch
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $453,944
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980470

## Citation

> US National Institutes of Health, RePORTER application 9980470, Adrenergic and GRK regulation of exosomes for cardiac regeneration (5P01HL134608-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9980470. Licensed CC0.

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