Local RyR2 Control

本地 RyR2 控制

• 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
• 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

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) 具有心脏毒性作用，急性 ETOH 暴露可导致心肌病和 急性 ETOH 可导致心律不齐和心房颤动 (AF)，占新发 AF 的三分之一。 病例与 ETOH 中毒有关 (1) 在诊所中，急性摄入大量乙醇后出现房颤。 ETOH（暴饮暴食）是假日心脏综合症（HHS）的基础，即意外房颤发作。从逻辑上讲，ETOH。 禁欲可降低房颤风险，但禁欲失败率较高，因此房颤复发率较高 打破急性 ETOH → AF 联系将被认为对临床有益。 口头禅“房颤引发房颤”（即房颤反复发作发展为持续性房颤）(2)。 预防或治疗急性 ETOH 驱动的 AF 的策略（除禁欲外）的一个障碍是细节很少。 我们小组最近对急性 ETOH 暴露与 AF 之间的分子机制尚不清楚。 发现急性 ETOH 通过激活应激激活的 c-Jun N 末端激酶 (JNK) 诱发 AF (3)。 激活的 JNK 然后磷酸化 Ca2+/钙调蛋白依赖性蛋白激酶 II (CaMKII)，进而磷酸化 磷酸化心脏兰尼碱受体 (RyR2)，增加 RyR2 的开放概率 (Po)。 信号级联最终促进舒张期 RyR2 介导的自发细胞内 Ca 释放事件 （火花/波）引发 AF (3) 我们的小组最近还发现卡维地洛，一种 FDA 批准的 β-。 肾上腺素能阻滞剂，对 RyR2 开口有直接作用 (4)，这限制了自发舒张 Ca 导致儿茶酚胺能多形性室性心动过速 (CPVT) 的波，这是一种致命的心室 心律失常、CPVT 和急性 ETOH 驱动的 AF 发生在结构正常的心脏中，并且具有 常见的病理生理学起源是异常自发的 RyR 介导的舒张期 Ca 释放。 限制这些自发事件，因此具有广泛的治疗前景，并且最初开发的药物是为了解决 CPVT 也可能有助于预防/治疗急性 ETOH 驱动的 AF。以下假设将得到检验。 ETOH 暴露通过作用于 RyR2-CamKII-JNK2 蛋白逐渐改变 RyR2 舒张功能 驻留在肌浆网 (SR) 膜上的复合物和新型非 𝛽 阻断卡维地洛 衍生物可以使急性 ETOH 驱动的 RyR2 功能障碍正常化 将使用多学科方法。 通过解决以下具体目标来检验这一假设 1) 定义连接 JNK 的分子机制。 激活和单一 RyR2 功能 2) 测试 RyR 靶向干预选项以限制异常。 急性 ETOH 暴露和基础 HHS 引起的自发舒张期 SR Ca 释放： 申请人将掌握单离子通道记录、结合测定和细胞内Ca的技术 申请人将在当地、国家和国际论坛上展示她的研究成果，并接受培训。 位于拉什大学医学中心生理学和生物物理学系的监督下 教授兼主席 Michael Fill 博士。