# Project 1:  Molecular Signalling in Cardiac Sarcomeres

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $421,294

## Abstract

Project Summary
Experiments proposed in Project 1 test the hypothesis that altered signaling at the level of sarcomeric proteins
is a significant element in maladaptation triggered by genetic and acquired hemodynamic stressors and an
important target for biased ligands as a therapeutic intervention. Strong synergistic interactions of Project 1
continue with other projects focused on sarcomere growth and remodeling (Project 2), and maladaptive
sarcomeric mechanisms related to control of cardiac dynamics (Project 3). Project 1 relies critically on the
support from Core B (Human Cell and Tissue) and Core C (Proteomics and Analytical Biochemistry). We focus
on maladaptive responses to stresses inducing dilated cardiomyopathy and the effects and mechanisms of
treatment with biased ligands, which signal specifically through β-arrestin via the angiotensin II receptor
(AT1R). Our lab is the first to report that unlike commonly used angiotensin receptor blockers (ARBs), eg.
Losartan, a biased ligand acting as an ARB is able to promote contractility via β-arrestin dependent sarcomere
signaling, which alters protein phosphorylation. In view of the potential for this mechanism to ameliorate the
progression to DCM, we propose to determine the effects and mechanisms of action of biased ligands as a
therapy for familial and acquired DCM. The Specific Aims are: Aim #1 To compare the ability of losartan and
biased ligands to reverse established maladaptations developed in mouse models of acquired and familial
DCM and in preparations from non-failing and failing human preparations (Core B). Aim #2 To determine the
mechanism(s) of the effects by which signaling via β-arrestin alters myofilament Ca-response and contractility.
Aim #3 To test the effectiveness of biased ligands on restoring structure and function of patient derived human
cardiac myocytes generated from inducible pluripotent stem cells (iPSC-CM) obtained from controls
(unaffected family members) and patients expressing DCM-linked mutant cardiac TnT-R173W. Our
approaches include readouts of EKG, echo-cardiography, P-V loops, blood pressure, apoptosis, biomarkers,
and tension/ intra-cellular Ca2+ transients; extensive proteomic analysis in conjunction with Core C; and,
established culture techniques and determination of intracellular [Ca2+], shortening and shortening velocity of
normal and cTnT mutant iPSC-CM cells. Our proposed studies investigate a novel mechanism of signaling to
sarcomeres with a strong potential for translation to therapies for DCM.

## Key facts

- **NIH application ID:** 9941109
- **Project number:** 5P01HL062426-20
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** R John Solaro
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,294
- **Award type:** 5
- **Project period:** — → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9941109

## Citation

> US National Institutes of Health, RePORTER application 9941109, Project 1:  Molecular Signalling in Cardiac Sarcomeres (5P01HL062426-20). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9941109. Licensed CC0.

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