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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：
10296019
负责人：
Benjamin Lears Prosser
金额：
$ 44.11万
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/10296019
关键词：
Address Affinity Age Animal Model Animals Binding Biotechnology Blood Circulation Calcium Cardiac Cardiac Myocytes Cardiology Cardiomyopathies Cells Clinical Clinical Trials Complement Contracts Cytoskeleton Disease Drug Kinetics EFRAC Enzymes Equilibrium 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 Pharmacology Phenotype Pilot Projects Population Post-Translational Protein Processing Prevalence Recording of previous events Relaxation Research Risk Rodent Science Scientist Specialist Speed Surgical Models Testing Therapeutic Tissues Tyrosine Work base clinical translation cohort experimental study gene therapy genetic approach heart cell heart function improved in vivo inhibitor/antagonist insight mortality mouse model mutant new therapeutic target novel novel therapeutics overexpression 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.

项目概要心力衰竭的一个常见且目前难以治疗的特征是心脏组织僵硬，从而损害心脏功能。心脏放松的能力。微管细胞骨架有助于心肌细胞的内部硬度，在某些条件下会阻碍心肌细胞收缩和舒张的能力。超过第一在 R01 的五年中，我们发现心肌细胞硬度受到翻译后严格调节微管的去酪氨酸化，并且去酪氨酸化的微管在人类心脏中持续升高衰竭，伴随心肌僵硬度增加。我们还发现，减少去酪氨酸微管足以降低心肌细胞的硬度并改善收缩和松弛来自不同形式的心力衰竭患者的心肌组织。我们进一步鉴定了该酶负责心脏中的去酪氨酸作用，并表明针对这种酶足以强有力地改善衰竭的人类心脏细胞的放松。因此，去酪氨酸形成了一种有前途的新治疗方法治疗心力衰竭的目标。拟议的研究将检验以下假设：遗传或小 “酪氨酸循环”的分子靶向可以稳定改善不同疾病的收缩和舒张功能心力衰竭的小型和大型动物模型。三个目标下的研究将涉及以下几个组成部分：这个假设。在目标 1 中，我们将探讨基因治疗方法是否过度表达酪氨酸化酶（TTL）足以改善遗传性心力衰竭小鼠模型的收缩功能，并改善射血分数保留的心力衰竭手术模型的舒张功能。目标2实验将专注于由新型高效小分子抑制剂组成的不同治疗方式去酪氨酸酶（VASH）。我们将评估这些新型抑制剂的药代动力学并进行测试它们在啮齿类动物和动物中减少去酪氨酸化和改善心脏功能的耐受性和功效人体细胞和组织。在目标 3 中，我们将把探索转向更大规模的动物研究，并测试是否靶向去酪氨酸足以改善肥厚猫的肌细胞和心肌功能心肌病和射血分数保留的心力衰竭。我们的跨物种、多尺度和多管齐下的方法将平衡我们的还原严谨性和综合相关性的目标，最终进一步临床转化。总之，这项工作将确定靶向去酪氨酸微管是否可以稳定地改善心力衰竭的心脏功能，并确定可能适合的治疗化合物进入临床管道。