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

• 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
• 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

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.

项目摘要/摘要 查加斯病是因感染而引起的心力衰竭的主要但不理解的感染原因 与锥虫Cruzi寄生虫一起。 T. Cruzi的全球流行率为700万，感染了30万以上 在美国的个人。查加斯疾病对医疗保健和经济造成了重大燃烧 每年总费用超过70亿美元。没有疫苗可用，当前治疗方案受到限制 晚期疾病的明显不良反应，长期治疗持续时间和效率差。新疗法 因此，世界卫生组织已将查加斯病的选择确定为研究的优先事项 组织，世界心脏联合会和美洲心脏病学会。我们的工作有 确定L-肉碱为急性和慢性T. cruzi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，仅具有良好的安全性并与之结合 抗寄生虫保健标准苯甲酸唑。 L-肉碱具有很高的临床转换性潜力 负担得起的，易于使用的，并且已经批准了FDA的治疗代谢疾病。但是， 目前尚不清楚L-肉碱在慢性T. cruzi感染中的作用机理。总体目标 该提议是为了阐明这种行动机制，在长期持续发展l- 肉碱进行临床实施，并鉴定了chagas的新替代治疗方案 疾病。 L-肉碱与经典的抗寄生虫不同，因为它改善了克鲁兹感染结果 不减少寄生虫负荷。这一点，结果也将扩大我们对Chagas疾病的理解 发病。该提议的核心假设是L-肉碱的作用机理是由 减少心脏脂肪酸氧化，增加心葡萄糖代谢，并降低感染诱导的 心脏收缩障碍。该中心假设将在慢性T. cruzi的实验模型中进行测试 感染，使用三个完整但独立的目标。我们将结合代谢组和 L-肉碱对脂肪酸氧化和葡萄糖氧化的影响的药理分析 （AIM 2）通过超声心动图分析L-肉碱治疗对心脏收缩性的影响（AIM 3）。 拟议的研究具有创新性，因为它围绕着新的候选治疗方案的焦点。 具有新型作用机理的疾病，这将导致鉴定chagas的其他途径 疾病治疗。拟议的研究很重要，因为它将导致对L-的严格理解 肉碱的作用机理，促进其向诊所的发展，并将确定新颖的候选者 进一步的查加斯病药物开发。总体而言，这项工作将提供有价值的新翻译 Chagas疾病治疗的途径，以及对心脏Chagas的重要基本见解 疾病发病机理。