Role of novel RNA binding protein LARP6 in alcoholic cardiomyopathy

新型RNA结合蛋白LARP6在酒精性心肌病中的作用

基本信息

批准号：
10593688
负责人：
Chandrasekar Bysani
金额：
$ 23.09万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10593688
关键词：
5&apos Untranslated Regions Adrenergic Agents Adrenergic beta-Agonists Alcohol abuse Alcoholic Cardiomyopathy Alcohols Animal Model Apoptosis Attenuated Binding Cardiac Cardiac Myocytes Cardiomyopathies Chronic Clinical Clinical Treatment Collagen Data Deposition Development Dilated Cardiomyopathy Dimensions Ethanol Fibrillar Collagen Fibroblasts Fibrosis Functional disorder Genetic Genetic Models Genetic study Goals Heart Injuries Heart failure Heavy Drinking Hepatic Stellate Cell Hypertension Hypertrophy Impairment In Vitro Inflammation Infusion procedures Intervention Intervention Studies Isoproterenol Knock-in Knock-in Mouse Left Left Ventricular Ejection Fraction Ligation Liver Fibrosis Messenger RNA Modeling Mus Mutant Strains Mice Mutate Myocardial dysfunction National Institute on Alcohol Abuse and Alcoholism Outcome Measure Oxidative Stress Pre-Clinical Model Prevention strategy Publishing RNA-Binding Proteins Rattus Regulation Resistance Ribonucleoproteins Risk Role Stress Structure Testing Therapeutic Therapeutic Uses Ventricular Wild Type Mouse bile duct cardioprotection coronary fibrosis crosslink drug-like compound heart damage high throughput screening in vivo interstitial mouse model new therapeutic target novel pharmacologic posttranscriptional prevent prophylactic protein expression response small molecule inhibitor stem targeted treatment treatment strategy vapor

项目摘要

Chronic excessive alcohol consumption can cause cardiac dysfunction and dilation, clinically termed alcoholic cardiomyopathy (AC). While chronic alcohol abuse alone causes AC, clinical evidence indicates that alcohol can exacerbate cardiac dysfunction resulting from other causes of cardiac injury or stress. Alcohol abuse also increases the risk of hypertension and heart failure, with as many as one third of all dilated cardiomyopathies attributed to AC. The development of cardiac fibrosis appears to be a key mechanism of AC dysfunction, as fibrosis impairs ventricular filling and impedes cardiomyocyte contraction. LARP6 is an RNA binding protein that upregulates collagen I expression post-transcriptionally by binding to the 5’SL structure and stabilizing the mRNA. Using a genetic knock-in mouse with modified 5’SL that prevents LARP6 binding, others have shown significantly decreased overall collagen expression and deposition in bile duct ligation-induced hepatic fibrosis. Stefanovic and colleagues discovered a drug-like compound, C9, that blocks the interaction between LARP6 and collagen I. They demonstrated that C9 inhibits collagen I expression in cultured hepatic stellate cells and prevented the development of fibrosis in animal models of hepatic fibrosis. Our preliminary studies indicate that both the knock-in 5’SL mouse and C9-treated wildtype mice are resistant to the development of cardiac fibrosis and dysfunction in response to chronic isoproterenol infusion. In the current proposal, using this unique genetic model and C9 compound, we will determine the role of LARP6 in AC. Our long-term goal is to identify the mechanisms responsible for alcohol-induced cardiac injury, which can then be targeted for clinical benefit. We hypothesize that blocking the interaction between LARP6 and collagen I mRNA significantly blunts cardiac remodeling (fibrosis and hypertrophy) and contractile dysfunction in a preclinical model of AC. Using the well- established NIAAA chronic+binge alcohol mouse model, we propose the following specific aims: Aim 1 determines whether blocking the interaction between LARP6 and collagen I in the 5’SL knock-in mice blunts alcohol abuse-induced adverse cardiac remodeling and dysfunction. We utilize integrated and systematic in vivo and in vitro approaches focused on ethanol-induced cardiac dysfunction, inflammation, oxidative stress, apoptosis, fibroblast activation, and fibrosis. Aim 2 investigates whether pharmacological blockade of LARP6 and collagen I interaction by the small molecule inhibitor C9 inhibits and/or reverses chronic alcohol abuse- induced cardiomyopathy. In this interventional approach, we will determine the therapeutic potential of C9 both prophylactically and therapeutically using the NIAAA model of AC. Outcome measures include cardiac diastolic and systolic function, ventricular chamber dimensions, collagen typing and cross-linking, inflammation, oxidative stress, and interstitial fibrosis. Our proposed genetic and interventional studies will determine if blocking LARP6 and collagen I interaction can blunt chronic alcohol-induced cardiomyopathy and serve as a potential novel therapeutic target for the treatment of clinical AC.

慢性过量饮酒会导致心脏功能障碍和词典，临床上称为酒精心肌病（AC）。虽然仅慢性酒精滥用会导致AC，但临床证据表明酒精通过心脏损伤或压力的其他原因导致的心脏功能障碍会加剧心脏功能障碍。酗酒也是如此增加了高血压和心力衰竭的风险，多达三分之一的扩张心肌病归因于交流。心脏纤维化的发展似乎是交流功能障碍的关键机制，如纤维化会损害心室填充并阻碍心肌细胞收缩。 LARP6是RNA结合蛋白通过结合5’SL结构并稳定在转录后上调胶原蛋白I mRNA。将遗传敲入小鼠与修改的5'sl防止LARP6结合，其他人已显示显着改善了胆管连接诱导的肝纤维化的总体胶原蛋白表达和沉积。 Stefanovic及其同事发现了一种类似药物的化合物C9，它阻止了LARP6之间的相互作用和胶原蛋白I.他们证明C9抑制了在培养的肝星状细胞和阻止了肝纤维化动物模型中纤维化的发展。我们的初步研究表明敲入5'SL小鼠和C9处理的野生型小鼠都对心脏纤维化的发展有抵抗力响应慢性异丙肾上腺素输注的功能障碍。在当前的建议中，使用此独特的通用模型和C9化合物，我们将确定LARP6在AC中的作用。我们的长期目标是确定导致酒精引起的心脏损伤的机制，然后可以针对临床益处。我们假设阻止LARP6和胶原蛋白I mRNA之间的相互作用明显更多的钝心脏 AC的临床前模型中的重塑（纤维化和肥大）和收缩功能障碍。使用井已建立的NIAAA慢性+暴饮暴食小鼠模型，我们提出以下特定目的：AIM 1 确定在5’SL敲入小鼠中是否阻止LARP6和胶原蛋白I之间的相互作用酒精滥用引起的不良心脏重塑和功能障碍。我们在体内和体外方法的重点是乙醇诱导的心脏功能障碍，感染，氧化应激，凋亡，成纤维细胞激活和纤维化。 AIM 2研究了LARP6的药物阻滞是否小分子抑制剂C9的胶原蛋白I相互作用抑制和/或逆转慢性酒精滥用 - 诱导心肌病。在这种介入方法中，我们将确定C9的治疗潜力使用AC的NIAAA模型进行预防和热。结果指标包括心脏舒张期和收缩功能，心室腔尺寸，胶原蛋白键入和交联，炎症，氧化应激和间质纤维化。我们提出的遗传和介入研究将确定是否是否阻止LARP6和胶原蛋白I相互作用可以钝化慢性酒精引起的心肌病，并用作潜在的新型治疗靶标用于治疗临床AC。