CaMKII signaling in physiology, heart failure and arrhythmias

生理学、心力衰竭和心律失常中的 CaMKII 信号传导

基本信息

  • 批准号:
    10335191
  • 负责人:
  • 金额:
    $ 96.36万
  • 依托单位:
  • 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:
    2018-01-22 至 2022-09-30
  • 项目状态:
    已结题

项目摘要

Abstract Heart failure and arrhythmias occur together, are marked by increased reactive oxygen species (ROS), and are major, unsolved public health problems. Despite this, ROS can be beneficial. However, clear molecular mechanisms supporting the benefits of ROS are lacking. The potential for ROS to be ‘good and bad’ is called the ROS paradox. This Outstanding Investigator Award application will propose innovative approaches to understanding and dissecting healthy from pathological ROS. The goal of this research program is to test a disruptive concept that ROS activation of the multifunctional calcium and calmodulin kinase II (CaMKII) by isoform and organelle selective pathways determine physiological and pathological outcomes of ROS signaling. We discovered that oxidation activates CaMKII (ox-CaMKII, Erickson Cell 2008) and established that ox-CaMKII, the major CaMKII isoform in heart, causes heart failure and arrhythmias. Our newest studies extended these findings to show that ox-CaMKII also contributes to asthma. In sharp contrast, our new preliminary data indicate that ox-CaMKII, an isoform enriched in skeletal muscle, is beneficial and enhances endurance, insulin sensitivity, lean phenotype, PGC-1, and expression or brain derived neurotrophic factor (BDNF), a myokine that improves exercise capacity and protects against myocardial injury. Our group discovered that CaMKII is present in mitochondria and that mitochondrial-targeted inhibition of CaMKII protects against common forms of myocardial injury associated with high ROS (Joiner Nature 2012). Here we propose to pursue new models of global (i.e. body-wide) mitochondrial CaMKII inhibition in flies (Drosophila melanogaster) and mice developed for the proposed OIA studies. Mitochondrial CaMKII inhibited flies have a prolonged lifespan and resistance to paraquat induced oxidant injury, while mice with global CaMKII inhibition have reduced mortality in sepsis and increased weight gain. We performed new phosphoproteomic and metabolic analyses that identified unanticipated mitochondrial CaMKII targets with central roles in metabolism and ROS production. Our preliminary computational modeling and experimental data suggest that physiological activation of mitochondrial CaMKII contributes to a beneficial metabolic fight or flight response that increases ATP; however, sustained and excessive mitochondrial CaMKII activity causes dilated cardiomyopathy due to loss of complex 1 and ATP deficiency. We and our collaborators will use state of the art computer modeling, imaging and metabolic studies, and generate a panel of mouse and Drosophila models using CRISPR/Cas9 to dissect contributions of CaMKII to specific targets relevant to heart failure, arrhythmias and to health. This research program requires an R35, or similar, mechanism because of its highly innovative concept that challenges current paradigms in CaMKII and ROS biology, the need to manage large amounts of data and generate new animals models, and the requirement for a prolonged timeframe.
摘要

项目成果

期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Myocardial death and dysfunction after ischemia-reperfusion injury require CaMKIIδ oxidation.
缺血再灌注损伤后的心肌死亡和功能障碍需要 CaMKIIδ 氧化。
  • DOI:
    10.1038/s41598-019-45743-6
  • 发表时间:
    2019
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Wu,Yuejin;Wang,Qinchuan;Feng,Ning;Granger,JonathanM;Anderson,MarkE
  • 通讯作者:
    Anderson,MarkE
HCN channels sense temperature and determine heart rate responses to heat.
HCN 通道感知温度并确定心率对热的反应。
  • DOI:
    10.1101/2023.09.02.556046
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wu,Yuejin;Wang,Qinchuan;Granger,Jonathan;Gaido,OscarReyes;Aguilar,EricNunez;Ludwig,Andreas;Moroni,Anna;Bianchet,MarioA;Anderson,MarkE
  • 通讯作者:
    Anderson,MarkE
Improving the sensitivity of in vivo CRISPR off-target detection with DISCOVER-Seq.
  • DOI:
    10.1038/s41592-023-01840-z
  • 发表时间:
    2023-05
  • 期刊:
  • 影响因子:
    48
  • 作者:
    Zou, Roger S.;Liu, Yang;Gaido, Oscar E. Reyes;Konig, Maximilian F.;Mog, Brian J.;Shen, Leo L.;Aviles-Vazquez, Franklin;Marin-Gonzalez, Alberto;Ha, Taekjip
  • 通讯作者:
    Ha, Taekjip
E-C coupling structural protein junctophilin-2 encodes a stress-adaptive transcription regulator.
  • DOI:
    10.1126/science.aan3303
  • 发表时间:
    2018-12-21
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Guo A;Wang Y;Chen B;Wang Y;Yuan J;Zhang L;Hall D;Wu J;Shi Y;Zhu Q;Chen C;Thiel WH;Zhan X;Weiss RM;Zhan F;Musselman CA;Pufall M;Zhu W;Au KF;Hong J;Anderson ME;Grueter CE;Song LS
  • 通讯作者:
    Song LS
Oxidative stress-induced autonomous activation of the calcium/calmodulin-dependent kinase II involves disulfide formation in the regulatory domain.
  • DOI:
    10.1016/j.jbc.2022.102579
  • 发表时间:
    2022-11
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Rocco-Machado, Nathalia;Lai, Lo;Kim, Geumsoo;He, Yi;Luczak, Elizabeth D.;Anderson, Mark E.;Levine, Rodney L.
  • 通讯作者:
    Levine, Rodney L.
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

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

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

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

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

MARK E ANDERSON其他文献

MARK E ANDERSON的其他文献

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

{{ truncateString('MARK E ANDERSON', 18)}}的其他基金

CaMKII signaling in physiology, heart failure and arrhythmias
生理学、心力衰竭和心律失常中的 CaMKII 信号传导
  • 批准号:
    10077577
  • 财政年份:
    2018
  • 资助金额:
    $ 96.36万
  • 项目类别:
CaMKII signaling in physiology, heart failure and arrhythmias
生理学、心力衰竭和心律失常中的 CaMKII 信号传导
  • 批准号:
    10026490
  • 财政年份:
    2018
  • 资助金额:
    $ 96.36万
  • 项目类别:
2014 Cardiac Regulatory Mechanisms Gordon Research Conference & Gordon Research S
2014年心脏调节机制戈登研究会议
  • 批准号:
    8784793
  • 财政年份:
    2014
  • 资助金额:
    $ 96.36万
  • 项目类别:
Mitochondrial Calmodulin Kinase II in Physiology and Disease
线粒体钙调蛋白激酶 II 在生理学和疾病中的作用
  • 批准号:
    8909894
  • 财政年份:
    2014
  • 资助金额:
    $ 96.36万
  • 项目类别:
CaMKII in Sinus Node Physiology and Disease
CaMKII 在窦房结生理学和疾病中的作用
  • 批准号:
    9115686
  • 财政年份:
    2014
  • 资助金额:
    $ 96.36万
  • 项目类别:
CaMKII in Sinus Node Physiology and Disease
CaMKII 在窦房结生理学和疾病中的作用
  • 批准号:
    8909874
  • 财政年份:
    2014
  • 资助金额:
    $ 96.36万
  • 项目类别:
CaMKII in Sinus Node Physiology and Disease
CaMKII 在窦房结生理学和疾病中的作用
  • 批准号:
    8915241
  • 财政年份:
    2014
  • 资助金额:
    $ 96.36万
  • 项目类别:
Mitochondrial Calmodulin Kinase II in Physiology and Disease
线粒体钙调蛋白激酶 II 在生理学和疾病中的作用
  • 批准号:
    8915239
  • 财政年份:
    2014
  • 资助金额:
    $ 96.36万
  • 项目类别:
2012 Cardiac Regulatory Mechanisms Gordon Research Conference and Gordon Research
2012年心脏调节机制戈登研究会议和戈登研究
  • 批准号:
    8316613
  • 财政年份:
    2012
  • 资助金额:
    $ 96.36万
  • 项目类别:
Oxidized CaMKII in Atrial Fibrillation
心房颤动中的氧化 CaMKII
  • 批准号:
    8628170
  • 财政年份:
    2012
  • 资助金额:
    $ 96.36万
  • 项目类别:

相似海外基金

DEVELOPING A HUMAN STEM CELL-DERIVED HEART MODEL TO CHARACTERIZE A NOVEL ARRHYTHMIA SYNDROME
开发人类干细胞衍生的心脏模型来表征新型心律失常综合征
  • 批准号:
    495592
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
Preliminary Study to Establish Heavy Ion Ablation Therapy for Lethal Ventricular Arrhythmia
重离子消融治疗致死性室性心律失常的初步研究
  • 批准号:
    23K14885
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Arrhythmia Mechanisms Modulated by Intercalated Disc Extracellular Nanodomains
闰盘细胞外纳米结构域调节心律失常的机制
  • 批准号:
    10668025
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
Development of a next-generation telemonitoring system for prognostic prediction of the onset of heart failure and arrhythmia
开发下一代远程监测系统,用于心力衰竭和心律失常发作的预后预测
  • 批准号:
    23K09597
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
The role of inflammation in the pathogenesis of atrial fibrillation: Implications for atrial remodeling pathophysiology and for early atrial arrhythmia recurrences following radiofrequency ablation and pulsed field ablation
炎症在心房颤动发病机制中的作用:对心房重塑病理生理学以及射频消融和脉冲场消融后早期房性心律失常复发的影响
  • 批准号:
    514892030
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
    WBP Fellowship
Improved arrhythmia ablation via MR-guided robotic catheterization and multimodal clinician feedback
通过 MR 引导的机器人导管插入术和多模式临床医生反馈改善心律失常消融
  • 批准号:
    10638497
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
Prototype development and validation of soft robotic sensor arrays for mapping cardiac arrhythmia
用于绘制心律失常的软机器人传感器阵列的原型开发和验证
  • 批准号:
    10722857
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
The role N-terminal acetylation in dilated cardiomyopathy and associated arrhythmia
N-末端乙酰化在扩张型心肌病和相关心律失常中的作用
  • 批准号:
    10733915
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
A novel regulator of Ca2+ homeostasis and arrhythmia susceptibility
Ca2 稳态和心律失常易感性的新型调节剂
  • 批准号:
    10724935
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
Novel Stellate Ganglia Chemo-ablation Approach to Treat Cardiac Arrhythmia and Cardiac Remodeling in Heart Failure
新型星状神经节化疗消融方法治疗心律失常和心力衰竭心脏重塑
  • 批准号:
    10727929
  • 财政年份:
    2023
  • 资助金额:
    $ 96.36万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了