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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：
9279248
负责人：
Benjamin Lears Prosser
金额：
$ 40.25万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279248
关键词：
Acute Affect Behavior Biochemical Biological Assay Biology Biophysics Cardiac Cardiac Myocytes Cell physiology Cells Cellular biology Clinical Collaborations Communication Complement Cytoskeleton Data Desmin Discontinuous Capillary Disease Elements Goals Health Heart Heart Diseases Heart failure Human Image Impairment Intermediate Filaments Kinesin Label Measures Mechanics Mediating Microtubules Modification Molecular Motor Muscle Cells Myocardial Myocardium Nature Patients Performance Physicians Post-Translational Protein Processing Publishing Regulation Research Resistance Resolution Rodent Role Scientist Stress Stretching Techniques Testing Therapeutic Tissues Transplantation Tubulin Tyrosine Viral Work alpha Tubulin crosslink density heart cell imaging genetics improved in vitro Assay insight mechanical properties mouse model novel spatial relationship tool

项目摘要

Project Summary: “Detyrosinated microtubules in cardiomyocyte mechanics” The microtubule cytoskeleton performs a number of cellular functions including cargo transport and structural support. In certain forms of heart disease there is an extensive proliferation and post-translational modification of the microtubule network that correlates with declining contractility. It has previously been suggested that the increased density of microtubules may provide an intrinsic mechanical resistance to cardiac contraction, and therefore that targeting microtubules may restore contractility in heart disease. However, a detailed mechanistic understanding of how microtubules provide resistance is lacking, and this line of research has stalled. The PI and colleagues have made two important advances to move this field forward. First, we have developed imaging and labeling tools to observe and characterize microtubule behavior in beating heart cells. We observe that microtubules function like springs in the beating heart, a challenge to the conventional view. These spring like microtubules provide a mechanical resistance to heart cell contraction and stretch. Second, we have identified a novel element that appears to regulate the mechanical properties of the cytoskeleton. In new published (Kerr et al. Nature Communications, 2015) and preliminary evidence we show that detyrosination, a post-translational modification of tubulin, regulates the compression-resistance of the cytoskeleton and alters the spring-like behavior of microtubules. Importantly, reducing detyrosination decreases mechanical resistance and increases myocyte contractility, suggesting a potential therapeutic benefit in heart disease. In this proposal we will thus test the hypothesis that detyrosination increases cytoskeletal compression resistance, and that specifically reducing detyrosination can improve contractility in heart failure. We have 3 major goals of our proposal: 1) to determine if increasing detyrosination is sufficient to impair myocyte mechanics; 2) to determine the molecular mechanism by which detyrosination influences cytoskeletal mechanics; 3) to determine if increased detyrosination impairs myocyte function in human heart disease. Our team of cardiomyocyte physiologists, cytoskeletal biologists, and a cardiac physician scientist are ideally suited to achieving these goals. The successful completion of this work will reveal mechanistic insight into how detyrosination alters cytoskeletal mechanics, a finding with broad relevance to cell biology and with specific translational implications for human cardiac disease.

项目总结: