# Detyrosinated microtubules in cardiomyocyte mechanics

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $441,085

## Abstract

Project Summary
A common and currently intractable feature of heart failure is the stiffening of cardiac tissue that impairs the
heart's ability to relax. The microtubule cytoskeleton contributes to the internal stiffness of heart muscle cells,
and under certain conditions can impede the ability of cardiomyocytes to both contract and relax. Over the first
five years of this R01, we found that cardiomyocyte stiffness is tightly regulated by post-translational
detyrosination of microtubules, and that detyrosinated microtubules are consistently elevated in human heart
failure, concomitant with increased myocardial stiffness. We also found that reducing detyrosinated
microtubules is sufficient to lower stiffness and improve contraction and relaxation in cardiomyocytes and
myocardial tissue from patients with diverse forms of heart failure. We further identified the enzyme
responsible for detyrosination in the heart, and showed that targeting this enzyme is sufficient to robustly
improve relaxation in failing human heart cells. As such, detyrosination forms a promising new therapeutic
target for the treatment of heart failure. The proposed research will test the hypothesis that genetic or small
molecule targeting of the “tyrosination cycle” can stably improve both systolic and diastolic function in different
small and large animal models of heart failure. Studies under three aims will address several components of
this hypothesis. In Aim 1, we will explore whether a gene therapy approach overexpressing the tyrosinating
enzyme (TTL) is sufficient to improve systolic function in a genetic mouse model of heart failure, and to
improve diastolic function in surgical model of heart failure with preserved ejection fraction. Aim 2 experiments
will focus on a different therapeutic modality consisting of novel and highly potent small molecule inhibitors of
the detyrosinating enzyme (VASH). We will evaluate the pharmacokinetics of these novel inhibitors and test
their tolerability and efficacy for reducing detyrosination and improving cardiac function in both rodent and
human cells and tissues. In Aim 3, we will move our exploration to larger animal studies and test whether
targeting detyrosination is sufficient to improve myocyte and myocardial function in cats with hypertrophic
cardiomyopathy and with heart failure with preserved ejection fraction. Our cross-species, multi-scale and
multi-pronged approach will balance our goals of reductionist rigor and integrative relevance that ultimately
furthers clinical translation. Together, this work will determine if targeting detyrosinated microtubules can stably
improve cardiac function in heart failure, and identify therapeutic compounds that may be suitable for
progression into a clinical pipeline.

## Key facts

- **NIH application ID:** 10296019
- **Project number:** 2R01HL133080-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Benjamin Lears Prosser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $441,085
- **Award type:** 2
- **Project period:** 2016-07-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10296019

## Citation

> US National Institutes of Health, RePORTER application 10296019, Detyrosinated microtubules in cardiomyocyte mechanics (2R01HL133080-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10296019. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*