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 恰加斯病是由感染引起的心力衰竭的主要感染性原因，但知之甚少。 带着克氏锥虫寄生虫。克鲁兹支原体在全球流行700万人，感染人数超过30万人。 在美国的个人。恰加斯病对医疗保健和经济造成重大负担 每年总成本超过70亿美元。没有疫苗可用，目前的治疗选择受到以下因素的限制 对晚期疾病副作用大、疗程长、疗效差。新疗法 因此，恰加斯病的治疗方案已被世界卫生组织确定为研究重点 世界心脏联合会和美洲心脏病学会。我们的工作已经完成 确定L-卡尼汀为治疗急慢性毛滴虫感染的新疗法，能够改善 心脏损害和疾病严重程度的读数，并单独和与 抗寄生虫护理标准苯硝唑。L-卡尼汀具有很高的临床可译性潜力， 负担得起，容易获得，并已获FDA批准用于治疗先天代谢紊乱。然而， L-卡尼汀治疗慢性毛滴虫感染的作用机制目前尚不清楚。总的目标是 这一建议就是为了阐明这一作用机制，使L能够长期持续发展-- 卡尼汀进入临床实施，并确定新的替代治疗方案查加斯 疾病。L-卡尼汀与经典抗寄生虫药的不同之处在于它改善了克氏毛滴虫的感染结局 而不会减少寄生虫的负载。因此，结果也将扩大我们对恰加斯病的理解 发病机制。这一提议的中心假设是L-卡尼汀的作用机制是由 减少心脏脂肪酸氧化，增加心脏葡萄糖代谢，降低感染诱导 心脏收缩功能受损。这一中心假设将在慢性克氏锥虫的实验模型中得到验证。 感染，使用三个相辅相成但独立的目标。我们将结合新陈代谢和 L肉碱对脂肪酸氧化(目标1)和葡萄糖氧化影响的药理分析 (目的2)超声心动图分析L-卡尼汀治疗对心肌收缩功能的影响(目的3)。 这项拟议的研究是创新的，因为它围绕着一种新的查加斯候选治疗方案 疾病具有新的作用机制，这将导致确定查加斯的其他途径 疾病治疗。这项拟议的研究具有重要意义，因为它将导致对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 进一步开发恰加斯病药物。总体而言，这项工作将提供有价值的新翻译 Chagas病治疗的途径以及对心脏Chagas的重要基础洞察 疾病发病机制。