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Detyrosinated microtubules in cardiomyocyte mechanics

心肌细胞力学中的去酪氨酸微管

基本信息

批准号：
10678948
负责人：
Benjamin Lears Prosser
金额：
$ 47.91万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678948
关键词：
Affinity Age Animal Model Animals Binding Biotechnology Calcium Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cells Circulation Clinical Clinical Trials Complement Contracts Cytoskeleton Disease Drug Kinetics EFRAC Enzyme Stability Enzymes Equilibrium Euthanasia Evaluation Exhibits Family Felidae Felis catus Functional disorder Future Gender Genetic Goals Heart Heart Hypertrophy Heart failure Human Hypertrophic Cardiomyopathy Impairment Industry Mechanics Microtubules Modality Modeling Modification Motion Mus Muscle Cells Myocardial Myocardial tissue Myocardium Noise Organ Donations Patients Phenotype Pilot Projects Population Post-Translational Protein Processing Prevalence Proliferating Recording of previous events Relaxation Research Rodent Science Scientist Specialist Speed Surgical Models Testing Therapeutic Tissues Work aorta constriction clinical translation cohort experimental study gene therapy genetic approach heart cell heart function improved in vivo inhibitor insight mortality mouse model mutant new therapeutic target novel novel therapeutics overexpression pharmacologic preservation pressure programs small molecule small molecule inhibitor targeted treatment therapeutic target

项目摘要

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.

项目总结

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness.

DOI：
10.3389/fphys.2021.696694
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Caporizzo MA;Prosser BL
通讯作者：
Prosser BL

Desmin intermediate filaments and tubulin detyrosination stabilize growing microtubules in the cardiomyocyte.

DOI：
10.1007/s00395-022-00962-3
发表时间：
2022-11-03
期刊：
Basic research in cardiology
影响因子：
9.5
作者：
通讯作者：

Extracellular stiffness induces contractile dysfunction in adult cardiomyocytes via cell-autonomous and microtubule-dependent mechanisms.

细胞外刚度通过细胞自主和微管依赖性机制引起成人心肌细胞的收缩功能障碍。

DOI：
10.1007/s00395-022-00952-5
发表时间：
2022-08-25
期刊：
Basic research in cardiology
影响因子：
9.5
作者：
通讯作者：

The microtubule cytoskeleton in cardiac mechanics and heart failure.

DOI：
10.1038/s41569-022-00692-y
发表时间：
2022-06
期刊：
Nature reviews. Cardiology
影响因子：
0
作者：
通讯作者：

Chronic activation of tubulin tyrosination in HCM mice and human iPSC-engineered heart tissues improves heart function.

HCM 小鼠和人类 iPSC 工程心脏组织中微管蛋白酪氨酸化的慢性激活可改善心脏功能。

DOI：
10.1101/2023.05.25.542365
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Pietsch,Niels;Chen,ChristinaYingxian;Kupsch,Svenja;Bacmeister,Lucas;Geertz,Birgit;Herera-Rivero,Marisol;Voß,Hanna;Krämer,Elisabeth;Braren,Ingke;Westermann,Dirk;Schlüter,Hartmut;Mearini,Giulia;Schlossarek,Saskia;vanderVelden,J
通讯作者：
vanderVelden,J