Local RyR2 Control

本地 RyR2 控制

• 批准号: 10116178
• 负责人: Catherine Carvajal
• 金额: $ 4.6万
• 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/10116178
• 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心肌病