Local RyR2 Control

本地 RyR2 控制

基本信息

批准号：
9909785
负责人：
Catherine Carvajal
金额：
$ 4.55万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
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：
2020-01-24 至 2022-01-23
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9909785
关键词：
Abstinence Academic Medical Centers Acute Address Adrenergic Antagonists Alcohol consumption Alcoholic Intoxication Anisomycin Arrhythmia Atrial Fibrillation Binding Biological Assay Biophysics Calcium Cardiac Cardiac Myocytes Cardiomyopathies Catecholaminergic Polymorphic Ventricular Tachycardia Cessation of life Chairperson Clinic Clinical Complex Consumption Dantrolene Data Diastole Ethanol Event Excision FDA approved Failure Flecainide Functional disorder Heart Heart failure Holidays Image Immunoprecipitation International Intervention Ion Channel Knowledge Lead Ligand Binding Link MAPK8 gene MAPK9 gene Mediating Membrane Microscopic Microsomes Molecular Monitor Muscle Cells N-terminal New Agents Oryctolagus cuniculus Outcome Pathogenicity Phosphorylation Phosphotransferases Physiology Population Probability Protein Biochemistry Proteins Recurrence Research Risk Ryanodine Ryanodine Receptor Calcium Release Channel SP600125 Saponins Sarcoplasmic Reticulum Signal Transduction Site Stress Structure Supervision Suspensions Syndrome Techniques Testing Therapeutic Time Titrations Toxic Actions Training Ventricular Arrhythmia alcohol abstinence alcohol exposure binge drinking calmodulin-dependent protein kinase II carvedilol channel blockers heart rhythm interdisciplinary approach kinase inhibitor novel operation prevent professor protein complex receptor function response

Abstinence Academic Medical Centers Acute Address Adrenergic Antagonists Alcohol consumption Alcoholic Intoxication Anisomycin Arrhythmia Atrial Fibrillation Binding Biological Assay Biophysics Calcium Cardiac Cardiac Myocytes Cardiomyopathies Catecholaminergic Polymorphic Ventricular Tachycardia Cessation of life Chairperson Clinic Clinical Complex Consumption Dantrolene Data Diastole Ethanol Event Excision FDA approved Failure Flecainide Functional disorder Heart Heart failure Holidays Image Immunoprecipitation International Intervention Ion Channel Knowledge Lead Ligand Binding Link MAPK8 gene MAPK9 gene Mediating Membrane Microscopic Microsomes Molecular Monitor Muscle Cells N-terminal New Agents Oryctolagus cuniculus Outcome Pathogenicity Phosphorylation Phosphotransferases Physiology Population Probability Protein Biochemistry Proteins Recurrence Research Risk Ryanodine Ryanodine Receptor Calcium Release Channel SP600125 Saponins Sarcoplasmic Reticulum Signal Transduction Site Stress Structure Supervision Suspensions Syndrome Techniques Testing Therapeutic Time Titrations Toxic Actions Training Ventricular Arrhythmia alcohol abstinence alcohol exposure binge drinking calmodulin-dependent protein kinase II carvedilol channel blockers heart rhythm interdisciplinary approach kinase inhibitor novel operation prevent professor protein complex receptor function response

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项目摘要

Ethanol (ETOH) has cardio toxic actions and acute ETOH exposure can lead to cardiomyopathy and death. Acute ETOH can result in irregular heart rhythms and atrial fibrillation (AF). A third of all new-onset AF cases are related to ETOH intoxication (1). In clinics, AF following acute consumption of high amounts of ETOH (binge drinking) underlies Holiday Heart Syndrome (HHS), unexpected AF onset. Logically, ETOH abstinence will reduce AF risk but the failure rate of abstinence is high and consequently AF recurrence is common in ETOH abusers. Breaking the acute ETOH → AF link would be beneficial considering the clinical mantra “AF begets AF” (i.e. repeated AF bouts progress to persistent AF) (2). There are no therapeutic strategies (besides abstinence) that prevent or treat acute ETOH-driven AF. One obstacle is that few details about the molecular mechanisms linking acute ETOH exposure and AF are unknown. Our group recently discovered acute ETOH evokes AF by activating the stress-activated c-Jun N-terminal kinase (JNK) (3). The activated JNK then phosphorylates Ca2+ /calmodulin-dependent protein kinase II (CaMKII) which in turn phosphorylates the cardiac ryanodine receptor (RyR2), increasing the RyR2’s open probability (Po). This signaling cascade ultimately promotes diastolic RyR2-mediated spontaneous intracellular Ca release events (sparks/waves) that initiate AF (3). Our group also recently found that Carvedilol, an FDA-approved β- adrenergic blocker, has a direct action on RyR2 openings (4) and this limits the spontaneous diastolic Ca waves that cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), a deadly ventricular arrhythmia. Interestingly, CPVT and acute ETOH-driven AF occur in structurally normal hearts and have a common pathophysiological origin, abnormal spontaneous RyR-mediated diastolic Ca release. Finding ways to limit these spontaneous events thus has broad therapeutic promise and agents originally developed to address CPVT may also help prevent/treat acute ETOH-driven AF. The following hypothesis will be tested. Acute ETOH exposure incrementally alters diastolic RyR2 function by acting on RyR2-CamKII-JNK2 protein complex resident on the sarcoplasmic reticulum (SR) membrane and novel non- 𝛽 blocking Carvedilol derivatives can normalize acute ETOH-driven RyR2 dysfunction. A multidisciplinary approach will be used to test this hypothesis by addressing the following specific aims. 1) Define molecular mechanism(s) linking JNK activation and single RyR2 function. 2) Test RyR-targeted intervention options to limit the abnormal spontaneous diastolic SR Ca release caused by acute ETOH exposure and underlying HHS. Training Plan: The applicant will master the techniques of single ion channel recordings, binding assays and intracellular Ca imaging. Applicant will present her research at local, national and international forums and her training will take place at Rush University Medical Center in the department of Physiology and Biophysics under the supervision of Professor and Chairman, Dr. Michael Fill.

乙醇（ETOH）具有有氧毒性作用，急性ETOH暴露会导致心肌病，并且死亡。急性ETOH会导致心律不规则和心房颤动（AF）。所有新的AF的三分之一病例与EtOH中毒有关（1）。在诊所中，急性消耗大量的AF ETOH（暴饮暴食）是假日心脏综合征（HHS）的基础，意外的AF发作。从逻辑上讲，etoh 禁欲会降低AF风险，但禁欲的失败率很高，因此AF的复发是在EtoH滥用者中常见。考虑到临床，打破急性ETOH→AF链接将是有益的咒语“ af begets af”（即反复的AF回弹发展到持续的AF）（2）。没有治疗性防止或治疗急性ETOH驱动的AF的策略（节制）。一个障碍是很少关于连接急性ETOH暴露和AF的分子机制尚不清楚。我们的小组最近发现急性ETOH通过激活应力激活的C-JUN N末端激酶（JNK）引起AF（3）。这然后激活的JNK磷酸化Ca2+ /钙调蛋白依赖性蛋白激酶II（CAMKII）磷酸化心脏ryanodine受体（RYR2），从而增加了RYR2的开放概率（PO）。这信号传导级联最终促进舒张期RYR2介导的赞助细胞内CA释放事件（火花/波）启动AF（3）。我们的小组最近还发现Carvedilol是FDA批准的β- 肾上腺素阻滞剂，对RYR2开口有直接的作用（4），这限制了舒张期CA 引起儿茶酚胺能多态性心脏心动过速（CPVT）的波浪，一种致命的心室心律不齐。有趣的是，CPVT和急性ETOH驱动的AF发生在结构正常的心脏中，并且具有常见的病理生理起源，异常赞助的RYR介导的舒张压CA释放。寻找方法因此，限制这些赞助事件具有广泛的治疗诺言，并且最初开发的代理人来解决 CPVT也可能有助于预防/治疗急性ETOH驱动的AF。将检验以下假设。急性 ETOH暴露通过作用于RyR2-Camkii-JNK2蛋白来逐步改变舒张性RYR2的功能肌质网（SR）膜上的复杂居民和新颖的非阻塞卡维迪洛衍生物可以使急性ETOH驱动的RYR2功能障碍标准化。将使用多学科的方法通过解决以下特定目标来检验这一假设。 1）定义连接JNK的分子机制激活和单个RYR2功能。 2）测试以RYR为目标的干预选项以限制异常由急性ETOH暴露和基础HHS引起的赞助舒张性SR CA释放。培训计划：申请人将掌握单个离子通道记录，绑定测定和细胞内CA的技术成像。申请人将在本地，国家和国际论坛上介绍她的研究，她的培训将接受在监督下，位于生理学与生物物理学系的拉什大学医学中心教授兼董事长迈克尔·菲尔（Michael Fill）博士。