# Role of the giant protein titin in cardiac health and disease

> **NIH NIH R35** · UNIVERSITY OF ARIZONA · 2020 · $884,369

## Abstract

Summary
This proposal focuses on titin, the largest protein known, in heart function and disease. Titin forms a novel and
multifunctional myofilament in the striated-muscle sarcomere with important roles that include regulating the
diastolic stiffness of the heart. Recent breakthrough studies revealed that titin is of high clinical importance in
both heart failure with preserved ejection fraction (HFpEF), and heart failure with reduced ejection fraction
(HFrEF). Although significant progress has been made in understanding the basic biology of titin, major gaps in
our understanding still remain, including a mechanistic understanding of how titin causes/contributes to heart
disease. An important focus of this proposal will be on titin’s role in diastolic dysfunction, motivated by recent
studies on patients with HFpEF that revealed deranged phosphorylation of titin’s molecular spring elements and
diastolic stiffening. The full spectrum of posttranslational modifications that occur in HFpEF will be studied and
high-resolution time-resolved spectroscopic techniques will focus on uncovering the structural changes in titin’s
spring elements triggered by posttranslational modification. Drug screens will focus on identifying compounds
that mimic or block these structural changes and functional studies will test whether newly discovered and
candidate drugs ameliorate titin-based diastolic stiffening in HFpEF. Post-transcriptional mechanisms will be
investigated as well, taking advantage of our recent work that has shown that splicing of titin can be manipulated
to upregulate complaint titin isoforms and restore diastolic function. The functional efficacy of identified
compounds will be tested on engineered heart tissues as well as on animal models. The second major focus of
this proposal will be on titin in HFrEF. Several recent sequencing studies in large groups of patients revealed
that mutations in the titin gene (TTN) are causative in ~20% of studied dilated cardiomyopathy (DCM) patients.
Many of the mutations are truncation mutations (TTNtv) and they have a preferential location in the A-band
segment of titin. The A-band segment is the least well-studied part of titin and an important goal of our research
is to critically examine the biology of titin in this region of the sarcomere where disease-causing mutations are
prominent. These studies include a focus on the role of titin in interacting with cMyBP-C (cardiac myosin-binding
protein C, a clinically important thick filament protein). Animal models will be investigated in which TTNtv have
been introduced in different regions of titin’s A-band segment. The effects of the mutations will be studied under
baseline conditions, when stressed, and when occurring in combination with mutations in other genes.
Importantly, we will also test whether excision of the mutated titin exons ameliorates titin-based DCM. In
summary, capitalizing on my >20-year track record of innovative titin research, and utilizing o...

## Key facts

- **NIH application ID:** 9904740
- **Project number:** 5R35HL144998-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Henk L. GRANZIER
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $884,369
- **Award type:** 5
- **Project period:** 2019-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904740

## Citation

> US National Institutes of Health, RePORTER application 9904740, Role of the giant protein titin in cardiac health and disease (5R35HL144998-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9904740. Licensed CC0.

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