CaMKII in Sinus Node Physiology and Disease

CaMKII 在窦房结生理学和疾病中的作用

基本信息

批准号：
8915241
负责人：
MARK E ANDERSON
金额：
$ 38.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-09 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915241
关键词：
ATP Synthesis Pathway Abbreviations American Angiotensin II Animal Model Apoptosis Arrhythmia Artificial cardiac pacemaker Boxing Bradycardia Cardiomyopathies Cell Death Cell physiology Cells Cessation of life Clinical Data Disease Disease Pathway Dominant-Negative Mutation Failure Feedback Figs - dietary Frequencies Functional disorder Funding Genetic Health Health Benefit Heart Heart Rate Heart failure Hypertension Implant Infection Infusion procedures Mechanics Mediating Mitochondria Modeling Morbidity - disease rate Mus Muscle Cells Myocardial Nature Nodal Operative Surgical Procedures Oxidative Stress Pacemakers Pathway interactions Patients Phosphorylation Physiological Physiology Play Public Health Reactive Oxygen Species Reagent Regulation Renin Reporting Role Sarcoplasmic Reticulum Signal Transduction Sinus Stress Sudden Death Testing Text Therapeutic Time Transgenic Organisms United States calmodulin-dependent protein kinase II fighting genetic approach high risk improved in vivo innovation mitochondrial dysfunction mitochondrial permeability transition pore mortality mouse model neglect novel prevent response

项目摘要

DESCRIPTION (provided by applicant): During the initial funding period, our group identified the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) as a necessary signal for physiological, 'fight or flight', increases in heart rate. We showed that the cellular mechanisms for CaMKII actions on heart rate were related to increasing sarcoplasmic reticulum Ca2+ leak but independent of the If 'pacemaker' current. We also found that excessive CaMKII activation contributed to sinoatrial nodal (SAN) dysfunction (SND) under conditions of increased oxidative stress, by increasing SAN cell apoptosis. SND causes symptomatic bradycardia and sudden death, particularly in patients and animal models with hypertension or heart failure, conditions marked by hyper-activation of the renin-angiotensin II (Ang II) signaling axis and elevated reactive oxygen species (ROS). Taken together, our studies show that CaMKII is important for physiological heart rate increases, but excessive CaMKII activity promotes SND. This dual role of CaMKII as a physiological and pathological signal has important parallels in myocardial physiology, where CaMKII may support the force-frequency response, and in disease, where excessive oxidized CaMKII (ox-CaMKII) contributes to cardiomyopathy and arrhythmias. We interpret emergent evidence in SAN to suggest that CaMKII inhibition slows heart rate, while protecting against excessive bradycardia due to SND in high risk clinical settings, modeled in mice by Ang II infusion. Our data suggest that CaMKII inhibition could eventually serve as a single, non-surgical therapy for regulating heart rate and preventing SND in high-risk patients. Our overall guiding hypothesis for this competitive renewal application is that CaMKII regulation of SAN mitochondria enhances physiological feedback to match energy demand with ATP synthesis and enable fight or flight heart rate increases, but excessive CaMKII activity results in mitochondrial Ca2+ overload that promotes SAN cell death and SND. We will test this innovative and novel mechanistic hypothesis using the following specific aims: Aim 1- Determine the role of mitochondrial CaMKII in SAN cell physiology and SND. Aim 2- Test the role of IMCU in SAN function and SND. Aim 3- Establish whether the MCU is a critical target for CaMKII effects on SAN physiology and SND.

描述（由申请人提供）：在最初的资金期间，我们的小组确定了多功能的Ca2+和钙调蛋白依赖性蛋白激酶II（CAMKII）是生理，“战斗或飞行”的必要信号，它增加了心率。我们表明，CAMKII对心率作用的细胞机制与增加的肌浆网Ca2+泄漏有关，但与“ Pacemaker”电流无关。我们还发现，在增加氧化应激的条件下，过度的CAMKII激活导致了辛里氏淋巴结（SAN）功能障碍（SND），通过增加SAN细胞凋亡。 SND会引起症状性心动过缓和猝死，尤其是在患有高血压或心力衰竭的患者和动物模型的情况下，肾素 - 血管紧张素II（ANG II）信号轴和活力升高的反应性氧（ROS）标志着。综上所述，我们的研究表明，CAMKII对于生理心率提高至关重要，但是过度的CAMKII活动会促进SND。 CAMKII作为生理和病理信号的双重作用在心肌生理学中具有重要的相似之处，在该生理学中，CaMKII可以支持力频率反应以及在疾病中，在该疾病中，过度氧化的CAMKII（OX-CAMKII）有助于心肌病变和心律失常。我们将SAN中的新兴证据解释为表明CAMKII抑制作用会减慢心率，同时防止高风险临床环境中的SND过度的心动过缓，这是通过ANG II输注在小鼠中模拟的。我们的数据表明，CAMKII抑制作用最终可以用作一种非手术治疗，用于调节心率并防止高危患者的SND。我们针对这种竞争性更新应用的总体指导假设是，CAMKII对San Mitochoncochia的调节增强了生理反馈，可以将能量需求与ATP合成与ATP合成并启用战斗或飞行心率增加，但CAMKII的过度活动会导致线粒体CA2+超负荷导致促进San Cell死亡和SND。我们将使用以下特定目的测试这种创新和新颖的机械假设：目标1-确定线粒体CAMKII在SAN细胞生理和SND中的作用。 AIM 2-测试IMCU在SAN功能和SND中的作用。 AIM 3-确定MCU是否是CAMKII对SAN生理学和SND影响的关键目标。