# Project 2

> **NIH NIH P01** · TEMPLE UNIV OF THE COMMONWEALTH · 2024 · $515,125

## Abstract

Project 2 (Koch)
SUMMARY/ABSTRACT
Studies have shown that the heart can secrete factors including those in extracellular vesicles (EVs)/exosomes
that can induce significant effects both locally to myocardial tissue and distantly to other organs. This includes
adipose tissue where data from our lab has revealed that the heart can secrete substances that can alter
adiposity, especially after a high fat diet (HFD). In fact, specific signals are released after HFD when adrenergic
signaling in myocytes is altered by manipulation of G protein-coupled receptor kinase 2 (GRK2) levels and activity
as increased myocyte GRK2 leads to a lean phenotype after HFD and myocyte-specific GRK2 inhibition leads
to an obese phenotype. This has been recapitulated in vitro with conditioned media experiments from myocytes
to cultured differentiating adipocytes. GRK2 regulates β-adrenergic receptors (βARs) in the heart where this
pathway is crucial for normal and compromised cardiac contractility and function. GRK2 is up-regulated in the
heart after cardiac stress, which includes HFD and increased GRK2 leads to compromised βAR signaling and
GRK2 is involved in heart failure (HF) progression. The GRK2-adrenergic signaling axis appears to be important
in the endocrine activity of the heart as well since we have uncovered data over the last cycle of this grant that
manipulation of GRK2 can have profound and significant effects on EV cargo including microRNAs (miRs). We
believe these EV/exosomes secreted from stressed hearts/myocytes with increased GRK2 could participate in
cardiac dysfunction locally. In addition to HFD, GRK2 can be increased in the hearts of mice by ischemic injury
and hypertrophic stress. Previous data and new data in this proposal not only shows that altering GRK2 in the
heart can have profound effects distantly on adipose tissue via what is secreted but also can affect local cardiac
cells in a paracrine fashion. In fact, increased cellular GRK2 results in increased GRK2 in secreted EV/exosomes
including after ischemic injury in vivo and these EVs have detrimental effects when placed on cultured cardiac
cells. Thus, manipulation of GRK2 in myocytes can significantly alter the myocardial secretome that appears to
have profound effects both locally and distantly including new data showing changes in fat depots after cardiac
injury in a sex-specific manner. Specifically, the Central Hypothesis of this proposal is that cardiac stressors,
which alters GRK2 levels and signaling can alter the myocardial secretome including the contents of
EV/exosomes, which can significantly affect myocardial injury and repair as well as influence regulation of distant
organs, especially adipose. Specific Aims are: [1] To identify factor(s) and elucidate novel mechanisms involved
in the communicative signals secreted from GRK2-altered myocardium responsible for regulating systemic
adiposity after HFD; [2] To determine the mechanistic role of altered myocyte GRK2 levels on EV/ex...

## Key facts

- **NIH application ID:** 10844904
- **Project number:** 2P01HL134608-06A1
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Walter J. Koch
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $515,125
- **Award type:** 2
- **Project period:** 2017-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844904

## Citation

> US National Institutes of Health, RePORTER application 10844904, Project 2 (2P01HL134608-06A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10844904. Licensed CC0.

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