CaMKII activation and regulation in adult cardiac myocytes

成人心肌细胞中 CaMKII 的激活和调节

基本信息

批准号：
10687251
负责人：
Donald M Bers
金额：
$ 72.12万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-18 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10687251
关键词：
Acute Adult Affect Affinity American Animals Arrhythmia Binding Binding Sites Biochemistry Ca(2+)-Calmodulin Dependent Protein Kinase Calcineurin Calcium Cardiac Cardiac Myocytes Cardiovascular Diseases Cells Chronic Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Data Defect Development Diabetes Mellitus EFRAC Failure Fatty acid glycerol esters Fluorescence Resonance Energy Transfer Functional disorder Gel Gene Expression Genetic Genetic Transcription Heart Heart failure Histone Deacetylase Homeostasis Hyperglycemia Image Individual Ion Channel Ions Knock-in Mouse Knowledge Link Measures Mediating Memory Metabolism Methylation Microfilaments Modeling Molecular Molecular Conformation Muscle Cells Mutation NG-Nitroarginine Methyl Ester Neurons Nitric Oxide Synthase Nuclear Pathologic Pathology Patients Phenotype Phosphorylation Phosphotransferases Play Post-Translational Protein Processing Process Production Proteins Regulation Reporter Resistance Role Site System Testing Therapeutic Therapeutic Intervention Tissues Transducers calmodulin-dependent protein kinase II diabetic falls heart function indium arsenide innovation mutant novel oxidation preservation pressure prevent response synergism targeted treatment

项目摘要

Project Summary/ Abstract Ca-Calmodulin dependent protein kinase (CaMKII) is an important regulator of cardiac function, and dysfunction in pathological states, regulating ion channels, Ca transporters, myofilaments and nuclear transcription. CaMKII may normally fine-tune these processes. But in pathological conditions like heart failure (HF), chronic autonomous CaMKII activation can over-phosphorylate targets, contributing to arrhythmogenesis due to acute effects on several ion channels and Ca- handling proteins. Chronic CaMKII activation is also a hallmark of several pathological states and acute or genetic CaMKII inhibition can reduce arrhythmias and the progression of HF. Thus understanding fundamental aspects of CaMKII regulation in cardiac myocytes is critical understanding dysfunction and potential therapeutics. We and others discovered several novel post-translational modifications (PTMs) that can trap CaMKII in an activated state, rather than turning on & off rapidly with local Ca transients. Autophosphorylation, oxidation, GlcNAcylation and S-nitrosylation within a regulatory hotspot on CaMKII creates memory and autonomous activity, even when Ca/CaM falls. There are also 3 PTMs at other sites that suppress CaMKII activation. Aims 1 and 2 will directly measure how these PTMs differentially affect activation and memory of CaMKII in adult cardiac myocytes, to fill a major knowledge gap in this field. Aim 3 will test whether CaMKII S-nitrosylation at a single site is required for the heart’s intrinsic response to increase Ca transients and contraction in response to acute and chronic pressure overload (or the Anrep effect). CaMKII has well-recognized roles in HF with reduced ejection (HFrEF), but its role in HF with preserved ejection (HFpEF) is unclear. Aim 4 will directly test the engagement of CaMKII in two new HFpEF models. The proposed studies will have major impact on our understanding of how CaMKII activity is regulated in heart, in ways that promote pathology and might be targets for therapeutic intervention.

项目摘要/摘要 Ca-钙调蛋白依赖性蛋白激酶（CAMKII）是心脏功能的重要调节剂，病理状态的功能障碍，调节离子通道，Ca转运蛋白，肌膜和核转录。 Camkii通常可以微调这些过程。但在病理上诸如心力衰竭（HF）之类的疾病，慢性自主CAMKII激活可能过度磷酸化靶标，由于对多个离子通道和CA-的急性影响而导致心律失常处理蛋白质。慢性CAMKII激活也是几种病理状态的标志急性或遗传CAMKII抑制可以减少心律不齐和HF的进展。那了解心肌细胞中CAMKII调节的基本方面至关重要了解功能障碍和潜在疗法。我们和其他人发现了几本小说翻译后修改（PTMS）可以将CAMKII置于激活状态，而不是用本地CA瞬变快速打开和关闭。自磷酸化，氧化，Glcnacylation CAMKII的监管热点内的S-亚硝基化创造记忆和自主活动，即使CA/CAM掉落也是如此。在其他站点也有3个PTMS抑制Camkii 激活。目标1和2将直接衡量这些PTM如何不同地影响激活和在成人心肌细胞中对CAMKII的记忆，以填补该领域的主要知识差距。目标3 将测试心脏内在的camkii s-硝基化是否需要单个位置响应急性和慢性压力的响应响应CA瞬变和收缩超负荷（或ANREP效果）。 Camkii在HF中具有良好的识别作用，射血降低（HFREF），但其在HF中的作用（HFPEF）尚不清楚。 AIM 4将直接测试 Camkii参与两种新的HFPEF型号。拟议的研究将产生重大影响关于我们对CAMKII活动的理解，以促进的方式调节病理学，可能是治疗干预的靶标。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuron-Restrictive Silencer Factor Limits Myocyte GαO Expression and Is Protective in Heart Failure Progression.

神经元限制性沉默因子限制肌细胞 GαO 表达并在心力衰竭进展中具有保护作用。

DOI：
10.1161/circresaha.121.320597
发表时间：
2022
期刊：
Circulation research
影响因子：
20.1
作者：
Sossalla,Samuel;Bers,DonaldM
通讯作者：
Bers,DonaldM

Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

DOI：
10.1016/j.yjmcc.2018.10.010
发表时间：
2018-12
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Wood BM;Simon M;Galice S;Alim CC;Ferrero M;Pinna NN;Bers DM;Bossuyt J
通讯作者：
Bossuyt J

CaMKII and PKA-dependent phosphorylation co-regulate nuclear localization of HDAC4 in adult cardiomyocytes.

CaMKII 和 PKA 依赖性磷酸化共同调节成体心肌细胞中 HDAC4 的核定位。

DOI：
10.1007/s00395-021-00850-2
发表时间：
2021-02-15
期刊：
Basic research in cardiology
影响因子：
9.5
作者：
Helmstadter KG;Ljubojevic-Holzer S;Wood BM;Taheri KD;Sedej S;Erickson JR;Bossuyt J;Bers DM
通讯作者：
Bers DM

Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.

DOI：
10.1126/sciadv.abg0927
发表时间：
2021-11-19
期刊：
Science advances
影响因子：
13.6
作者：
Morotti S;Liu C;Hegyi B;Ni H;Fogli Iseppe A;Wang L;Pritoni M;Ripplinger CM;Bers DM;Edwards AG;Grandi E
通讯作者：
Grandi E

Mechanoelectric coupling and arrhythmogenesis in cardiomyocytes contracting under mechanical afterload in a 3D viscoelastic hydrogel.

DOI：
10.1073/pnas.2108484118
发表时间：
2021-08-03
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Hegyi B;Shimkunas R;Jian Z;Izu LT;Bers DM;Chen-Izu Y
通讯作者：
Chen-Izu Y

DOI：
{{ item.doi }}
发表时间：
{{ item.publish_year }}
期刊：
{{ item.journal_name }}
影响因子：
{{ item.factor }}
作者：
{{ item.authors }}
通讯作者：
{{ item.author }}

数据更新时间：{{ journalArticles.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ monograph.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ sciAawards.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ conferencePapers.updateTime }}

作者：
{{ item.author }}

数据更新时间：{{ patent.updateTime }}

Donald M Bers其他文献

The Difference of Calmodulin-Ryanodine Receptor Affinity Between N-terminal, Central and C-terminal RyR2-CPVT Knock-in Mice

N端、中央端和C端RyR2-CPVT敲入小鼠钙调蛋白-兰尼定受体亲和力的差异

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Hitoshi Uchinoumi;Xiaoqiong Dong;Ivanita Stefanon;Mena Said;Rogerio Faustino;Razvan L Cornea;Univ of Minnesota;Xander H.t. Wehrens; Takeshi Yamamoto;Masafumi Yano;Donald M Bers
通讯作者：
Donald M Bers