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Post-translational mechanisms of cardiac adaptation during unloading

卸载过程中心脏适应的翻译后机制

基本信息

批准号：
10199034
负责人：
Christopher Solis-Ocampo
金额：
$ 10.48万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10199034
关键词：
Acetylation Acute Affect Atrophic Biochemistry Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Size Cells Cessation of life Chemicals Chicago Data Deacetylation Dependovirus Devices Dominant-Negative Mutation Dose Environment Enzymes Equilibrium Goals HDAC3 gene Heart Histone Deacetylase Histone Deacetylase Inhibitor Hormonal Human Hypertrophic Cardiomyopathy Hypertrophy Illinois Intervention Journals Knowledge Lead Left Lysine Malignant Neoplasms Mass Spectrum Analysis Mechanics Mentors Methods Modeling Modification Molecular Mus Muscle Proteins Myocardial Myosin ATPase Normal Cell Oligonucleotides Outcome Pathology Pathway interactions Periodicity Phase Physiological Physiology Post-Translational Protein Processing Process Proteins Proteomics Publications Rattus Regulation Research Research Personnel Rest Sarcomeres Signal Pathway Site Small Interfering RNA Stimulus Structure Testing Training Ubiquitin Ubiquitination Universities Ventricular Weight Lifting Work actin capping protein alpha Actinin base career career development constriction dosage extracellular gel electrophoresis heart cell hemodynamics induced pluripotent stem cell inhibitor/antagonist innovation mechanical load mouse model muscle form overexpression programs protein degradation proteostasis response sarcopenia

项目摘要

PROJECT SUMMARY Cardiovascular diseases are responsible for more deaths each year than cancer, which is why it is important to study how to keep hearts healthy. Hearts undergo physiological remodeling; this is a structural and functional adjustment that matches contractile capacity to hemodynamic demand. In cardiomyocytes, hormonal and mechanosensitive signaling pathways maintain the balance between normal cell size, hypertrophy, or atrophy. Pathologies develop when the adequate adaptation to a stimulus is mismatched. My long-term goal is to establish an independent research program on understanding how mechanical load affects myocardial structure and function and what are the contributing molecular mechanisms. My recent publication in the Journal of General Physiology shows that changing mechanical stimulus of cardiac myocytes affects the dynamics and post-translational modification of the Z-disc actin-capping protein CapZ. I wish to extend this in a new direction working as an independent investigator. Accordingly, my central hypothesis is that mechanical load of cardiomyocytes regulates protein homeostasis in sarcomeres through the balance between acetylation and ubiquitination of lysine residues. Histone deacetylase 3 (HDAC3) is one known acetylation enzyme of sarcomeric proteins. I focus on the Z-disc proteins CapZ and α-actinin because they both maintain sarcomere integrity and because acetylation sites have been previously found in both proteins. My preliminary data shows that unloading changes the relative abundance of CapZ and α-actinin ubiquitination and acetylation. The goal of the K99 mentored phase is (1) to determine post-translational modifications arising from chemical or mechanical unloading of isolated cardiomyocytes with focus on acetylation and K48-oligo-ubiquitination. The goals of the R00 independent phase are (2) to characterize how HDAC3 activity in cardiomyocytes regulates α-actinin and CapZ deacetylation with varying mechanical load and (3) to determine the changes in post- translational modification of sarcomeric proteins by HDAC3 during left-ventricular unloading in whole hearts. The innovation of this project lies in the combination of cardiomyocyte mechanobiology with post-translational molecular biochemistry to understand how cardiac cells maintain sarcomeric protein balance through the ubiquitin-acetylation pathway in response to mechanical stimuli. The outcomes of this project will expand our knowledge about the signaling pathways responsible for modulating protein homeostasis in cardiomyocytes that may develop new research lines for regulation in hypertrophic cardiomyopathies and sarcopenia. The career development activities in this proposal, in addition to the exceptional mentoring team and research environment at the University of Illinois at Chicago, will support my successful transition to a career as an independent investigator.

项目总结心血管疾病每年导致的死亡人数超过癌症，这就是为什么研究如何保持心脏健康。心脏经历生理性重塑；这是一种结构性和功能性的使收缩能力与血流动力学需求相匹配的调整。在心肌细胞中，激素和机械敏感信号通路维持正常细胞大小、肥大或萎缩之间的平衡。当对刺激的充分适应不匹配时，就会发生病理。我的长期目标是建立了解机械负荷如何影响心肌的独立研究计划结构和功能，以及什么是贡献的分子机制。我最近在普通生理学杂志显示，改变心肌细胞的机械刺激会影响 Z-Disc肌动蛋白封端蛋白CAPZ的动力学和翻译后修饰。我希望将其扩展到一个新方向以独立调查员的身份工作。因此，我的中心假设是机械的心肌细胞负荷通过乙酰化之间的平衡调节肌瘤内蛋白质的动态平衡和赖氨酸残基的泛素化。组蛋白脱乙酰基酶3(HDAC3)是一种已知的肌节蛋白。我主要研究Z-Disc蛋白CAPZ和α-Actinin，因为它们都维持着肌节这是因为之前在这两种蛋白质中都发现了乙酰化位点。我的初步数据显示这种卸载改变了CAPZ和α-肌动蛋白的相对丰度，泛素化和乙酰化。目标是 K99指导阶段的目的是(1)确定由化学或机械卸载分离的心肌细胞，重点是乙酰化和K48-寡泛素化。这个 R00非依赖性阶段的目标是：(2)研究心肌细胞中HDAC3活性如何调节 α-肌动蛋白和CAPZ脱乙酰化在不同的机械负荷和(3)测定后的变化全心左室卸载过程中HDAC3对肌瘤蛋白的翻译修饰。本项目的创新之处在于将心肌细胞力学生物学与翻译后研究相结合分子生物化学以了解心肌细胞如何通过机械刺激下的泛素-乙酰化途径。该项目的成果将扩大我们的对调控心肌细胞蛋白质稳态的信号通路的认识这可能会为肥厚性心肌病和骨质疏松症的调控开辟新的研究路线。这个本提案中的职业发展活动，除了出色的指导团队和研究在芝加哥伊利诺伊大学的环境，将支持我成功地过渡到职业生涯独立调查员。