# Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $468,182

## Abstract

Project Summary:
The cardiac thin filament is the essential regulator of cardiac contractility and relaxation
at the molecular level. It is comprised of five discrete proteins: cTnC, cTnI, cTnT, actin
and tropomyosin that have co-evolved to sustain efficient cardiac performance at rest,
during exercise and, importantly, to respond to pathologic stressors. Mutations in genes
encoding each of these proteins have been definitively linked to the development of a
range of human genetic cardiomyopathies, including hypertrophic (HCM) and dilated
(DCM) forms. Despite 25 years of study to define the direct link(s) between the
biophysical insult and the resultant complex cardiomyopathy, many questions remain
and significantly limit our ability to use genotype to prognosticate and inform patient
management. Recent clinical studies based on genotyped cohorts have established that
the earliest stages of pathogenic remodeling precedes the development of overt cardiac
hypertrophy or dilatation. This seminal observation raises the possibility that early
therapeutic intervention focusing on the earliest molecular “triggers” may prove
successful in slowing the natural history of these complex disorders. To test this
hypothesis, the current application builds on our prior funding period where we
developed an innovative integrated approach to probing thin filament-linked HCM and
DCM that incorporates computation, biophysics and whole-heart physiology. We have
identified two distinct, common pathogenic pathways to study. In Aim 1 we will delineate
the dynamic role of the Tropomyosin overlap domain and the coupled allosteric
regulation by the cardiac Troponin T N terminus on the differential cardiac remodeling
that defines hypertrophic and dilated cardiomyopathies linked to known mutations in the
flexible tropomyosin overlap. And in Aim 2 we will define the potential modulatory role of
altered cTnC Ca2+ dissociation kinetics in the activation of CaMKII signaling as a nodal
point in the pathogenesis of sarcomeric hypertrophic cardiomyopathy. The successful
completion of these Aims will both reveal novel disease mechanisms and directly test
the potential for altering the natural history of genetic HCM and DCM.

## Key facts

- **NIH application ID:** 9840923
- **Project number:** 5R01HL075619-16
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Jil C Tardiff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $468,182
- **Award type:** 5
- **Project period:** 2003-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840923

## Citation

> US National Institutes of Health, RePORTER application 9840923, Integrative Approach to Divergent Remodeling in Thin Filament Cardiomyopathies (5R01HL075619-16). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9840923. Licensed CC0.

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