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

项目概要/摘要 查加斯病是一种主要的但知之甚少的感染性心力衰竭原因，由感染引起 克氏锥虫寄生虫T. cruzi在全世界的患病率为700万，感染人数超过30万 在美国的个人。恰加斯病给卫生保健和经济造成重大负担 每年的总成本超过70亿美元。没有可用的疫苗，目前的治疗选择受到限制， 不良反应明显，治疗时间长，晚期疾病疗效差。新的治疗 因此，世界卫生组织已将治疗恰加斯病的方案确定为优先研究项目。 组织，世界心脏联合会和美洲心脏病学会。我们的工作 确定L-肉毒碱作为急性和慢性T. cruzi感染，能够改善 心脏损伤和疾病严重程度的读数，以及单独和与 抗寄生虫的标准治疗药物苄硝唑左旋肉碱具有很高的临床可翻译性潜力， 价格实惠、易于获得，并且已获得FDA批准用于治疗先天性代谢障碍。但 左旋卡尼汀治疗慢性T.目前尚不清楚cruzi感染的情况。的总体目标 该建议旨在阐明这种作用机制，使L- 卡尼汀进入临床实施，并确定新的替代治疗方案，南美锥虫病 疾病左旋肉碱不同于经典的抗寄生虫药，因为它提高T。Cruzi感染结局 而不减少寄生负载。因此，研究结果也将扩大我们对恰加斯病的理解 发病机制该建议的中心假设是，左旋肉碱的作用机制是介导的 减少心脏脂肪酸氧化，增加心脏葡萄糖代谢，降低感染诱导的 心脏收缩功能障碍这一中心假设将在慢性T。cruzi 感染，使用三个互补但独立的目标。我们将联合收割机结合代谢组学和 L-肉碱对脂肪酸氧化（目的1）和葡萄糖氧化影响的药理学分析 (aim 2）超声心动图分析左旋卡尼汀治疗对心肌收缩力的影响（目的3）。 这项拟议中的研究是创新的，因为它围绕着一个新的候选治疗方案查加斯 这种疾病具有新的作用机制，它将导致查明查加斯病的其他途径 疾病治疗。这项研究具有重要意义，因为它将导致对L- 肉毒碱的作用机制，促进其进展到临床，并将确定新的候选人， 进一步开发恰加斯病药物。总的来说，这项工作将提供有价值的新的翻译 查加斯病治疗的途径，以及对心脏查加斯病的重要基本见解 发病机理

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.