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，急性接触Etoh可导致心肌病和 死亡。急性无水乙醇可导致心律不齐和房颤(AF)。三分之一的新发房颤患者 2例与乙醇中毒有关(1例)。在临床上，由于急性摄入大量的 酒精(酗酒)是假日心脏病综合症(HHS)的基础，也是房颤意外发作的原因。从逻辑上讲，Etoh 禁欲会降低房颤的风险，但禁欲的失败率很高，因此房颤复发 在酒精滥用者中很常见。考虑到临床情况，打破急性ETH→房颤链接将是有益的 口头禅“房颤产生房颤”(即反复房颤发作进展为持续性房颤)(2)。没有治疗的方法 预防或治疗急性无水乙醇引起的房颤的策略(除禁欲外)。一个障碍是细节很少 关于急性乙醇暴露与房颤之间的分子机制尚不清楚。我们的小组最近 发现急性无水乙醇通过激活应激激活的c-jun氨基末端激酶(JNK)引起房颤(3)。这个 激活JNK然后磷酸化钙/钙调素依赖的蛋白激酶II(CaMKII)，进而 使心肌兰尼定受体(RyR2)磷酸化，增加RyR2‘S开放概率(Po)。这 信号级联最终促进舒张期RyR2介导的自发性细胞内钙释放事件 (火花/波)，引发房颤(3)。我们的团队最近还发现，卡维地洛，一种FDA批准的β- 肾上腺素能阻滞剂对RyR2的开放有直接作用(4)，这限制了自发的舒张期 引起儿茶酚胺能多形性室性心动过速(CPVT)的波，一种致命的室性心动过速 心律不齐。有趣的是，CPVT和急性无水乙醇驱动的房颤发生在结构正常的心脏中，并有 共同的病理生理来源，异常自发的RyR介导的舒张期钙释放。想方设法 因此，限制这些自发事件具有广泛的治疗前景，最初开发的药物是为了解决 CPVT也可能有助于预防/治疗急性无水乙醇引起的房颤。以下假设将得到检验。急性 乙醇暴露通过作用于RyR2-CaMKII-JNK2蛋白而逐渐改变RyR2的舒张期功能 肌浆网膜上的复合体与新型非𝛽阻滞剂卡维地洛 衍生物可以使急性乙醇驱动的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)明确JNK连接的分子机制(S) 激活和单一的RyR2功能。2)测试RyR-靶向干预选项以限制异常 急性乙醇暴露和潜在的HHS引起的舒张期自发性SR钙释放。培训计划： 申请者将掌握单离子通道记录、结合分析和细胞内钙离子的技术 成像。申请者将在当地、国家和国际论坛上展示她的研究成果，她的培训将包括 在拉什大学医学中心的生理和生物物理系的监督下 教授兼主席迈克尔·菲尔博士。