Deciphering the mechanism of action of carnitine, a novel treatment for chronic Chagas disease

破译肉碱的作用机制，一种治疗慢性恰加斯病的新方法

基本信息

批准号：
10663997
负责人：
Laura-Isobel McCall
金额：
$ 13.06万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-12 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10663997
关键词：
Acute Address Adverse effects Affect American Amino Acids Antiparasitic Agents Benznidazole Biological Assay Biological Markers Brain natriuretic peptide Carbohydrates Cardiac Cardiac health Cardiology Carnitine Cell Respiration Chagas Disease Chronic Clinic Clinical Complementary therapies Data Development Disease Disease model Echocardiography Esters Experimental Models FDA approved Fatty Acids Funding Generations Glucose Goals Healthcare Heart Heart Diseases Heart Transplantation Heart failure Impairment In Vitro Individual Infection Knowledge Laboratories Lesion Levocarnitine Mediating Metabolic Metabolic Diseases Metabolic Pathway Mission Mitochondria Mus Myocardial Outcome Parasites Pathogenesis Pathway interactions Patients Persons Prevalence Publishing Research Research Priority Role Safety Severities Severity of illness Site Societies Structure Symptoms Testing Therapeutic Tissues Treatment Protocols Trypanosoma cruzi United States United States National Institutes of Health Work World Health Organization acylcarnitine alternative treatment bench-to-bedside translation chronic infection clinical care clinical development clinical implementation clinical translation cost drug development effective therapy fatty acid metabolism fatty acid oxidation glucose metabolism heart damage heart function heart metabolism improved in vivo innovation insight metabolic abnormality assessment metabolomics mortality novel oxidation pharmacologic preclinical development prevent protective effect pyruvate dehydrogenase standard of care treatment duration treatment strategy vaccine access

项目摘要

Project summary/abstract Chagas disease is a leading but poorly-understood infectious cause of heart failure, resulting from infection with Trypanosoma cruzi parasites. T. cruzi has a worldwide prevalence of 7 million, with over 300,000 infected individuals in the United States. Chagas disease causes a significant burden on health care and the economy of over $7 billion annually in total costs. No vaccines are available, and current treatment options are limited by significant adverse effects, long treatment duration, and poor efficacy in late-stage disease. New treatment options for Chagas disease have therefore been identified as a research priority by the World Health Organization, the World Heart Federation, and the Inter-American Society of Cardiology. Our work has identified L-carnitine as a novel treatment regimen for acute and chronic T. cruzi infection, able to improve readouts of cardiac damage and disease severity, and with a good safety profile alone and in combination with the antiparasitic standard-of-care benznidazole. L-carnitine has high potential for clinical translatability, being affordable, readily available, and already FDA-approved to treat inborn metabolic disorders. However, the mechanism of action of L-carnitine in chronic T. cruzi infection is currently unknown. The overall objective of this proposal is to elucidate this mechanism of action, enabling in the long-term continued development of L- carnitine into clinical implementation, and the identification of new alternative treatment regimens for Chagas disease. L-carnitine differs from classic antiparasitic agents in that it improves T. cruzi infection outcomes without reducing parasite load. Thus, results will also expand our understanding of Chagas disease pathogenesis. The central hypothesis of this proposal is that L-carnitine’s mechanism of action is mediated by lessening cardiac fatty acid oxidation, increasing cardiac glucose metabolism, and lowering infection-induced cardiac contractile impairment. This central hypothesis will be tested in experimental models of chronic T. cruzi infection, using three complementary yet independent aims. We will combine metabolomic and pharmacological analyses of the impact of L-carnitine on fatty acid oxidation (aim 1) and on glucose oxidation (aim 2) with echocardiographic analyses of the impact of L-carnitine treatment on cardiac contractility (aim 3). The proposed research is innovative because it centers around a new candidate treatment regimen for Chagas disease with novel mechanism of action, and it will lead to the identification of additional avenues for Chagas disease treatment. The proposed research is significant because it will lead to a rigorous understanding of L- carnitine’s mechanism of action, facilitating its progression to the clinic, and will identify novel candidates for further Chagas disease drug development. Overall, this work will provide valuable new translational avenues for Chagas disease treatment, as well as significant fundamental insight into cardiac Chagas disease pathogenesis.

项目概要/摘要恰加斯病是由感染引起的心力衰竭的主要但人们知之甚少的感染原因克氏锥虫 (T. cruzi) 在全球范围内的患病率达 700 万，感染人数超过 300,000 人。恰加斯病给美国的医疗保健和经济造成了巨大的负担。每年的总成本超过 70 亿美元，目前尚无可用的疫苗，而且目前的治疗方案也受到以下因素的限制。不良反应显着，治疗时间长，疾病晚期疗效差。因此，世界卫生组织已将恰加斯病的治疗方案确定为研究重点我们的工作包括世界心脏联合会和美洲心脏病学会。确定左旋肉碱是一种治疗急性和慢性克氏锥虫感染的新型治疗方案，能够改善心脏损伤和疾病严重程度的读数，单独或与其他药物结合使用具有良好的安全性抗寄生虫护理标准苯并硝唑具有很高的临床转化潜力，价格实惠、容易获得且已获得 FDA 批准用于治疗先天性代谢紊乱。左旋肉碱在慢性克氏锥虫感染中的作用机制目前尚不清楚。该提案旨在阐明这种作用机制，从而实现L-的长期持续发展肉毒碱进入临床实施，并确定新的恰加斯替代治疗方案左旋肉碱与经典抗寄生虫药的不同之处在于它可以改善克氏锥虫感染的结果。因此，结果也将扩大我们对恰加斯病的了解。该提议的中心假设是左旋肉碱的作用机制是由减少心脏脂肪酸氧化，增加心脏葡萄糖代谢，并降低感染引起的这一中心假设将在慢性克氏锥虫实验模型中得到检验。感染，使用三个互补但独立的目标，我们将结合代谢组学和左旋肉碱对脂肪酸氧化（目标 1）和葡萄糖氧化影响的药理学分析（目标 2）通过超声心动图分析左旋肉碱治疗对心肌收缩力的影响（目标 3）。拟议的研究具有创新性，因为它围绕一种新的恰加斯候选治疗方案具有新作用机制的疾病，这将导致查加斯病的其他途径的确定拟议的研究意义重大，因为它将带来对 L- 的严格理解。肉碱的作用机制，促进其进入临床，并将确定新的候选药物总体而言，这项工作将提供有价值的新转化。恰加斯病的治疗途径，以及对心脏恰加斯病的重要基础见解疾病发病机制。