Small molecule biomarkers of cardiac Chagas disease progression

项目摘要/摘要 克氏锥虫寄生虫是恰加斯病(CD)的病原体，影响着500-600万人 全世界的人，仅在美国就有超过30万人。20%至30%的克氏毛滴虫感染者 发展出导致心力衰竭的症状性疾病，使其在拉丁语中成为心力衰竭的重要原因 美国。目前，临床医生还没有可用的工具来预测哪些患者将发展为严重的 疾病和不会的疾病。拉美流行国家的护理标准是治疗所有受感染的儿童； 然而，对于无症状成人的治疗还没有达成共识。目前疾控中心的指导方针建议 治疗50岁或50岁以下尚未出现严重症状的克氏支原体阳性患者；治疗是 50岁以上的患者可选，因为副作用风险很高，即使成年人年龄在51岁及以上 占所有CD患者的四分之一。CD治疗方案耐受性差，高达30%的患者 因副作用未能完成完整疗程的治疗。治疗所有感染者会暴露出 ~70%的克氏毛滴虫感染者永远不会有危险的临床表现 无缘无故吸毒。一种预测结果的生物标志物将帮助临床医生和他们的患者权衡治疗 风险和好处，识别高危患者以加强监测和随访，从而导致更高的患者 依从性和治疗完成，同时避免那些不太可能患心脏病的人 不必要的药物毒性。进展生物标记物也将促进新型CD的临床试验 治疗学。我们最近的研究表明，心脏小分子图谱在重症患者之间存在差异。 以及在老鼠和非人类灵长类动物中的轻微感染。主要差异代谢物包括酰肉碱家族 在慢性CD小鼠模型中，其成员的数量也因血清感染而减少。在此基础上 根据初步数据，我们假设血清小分子将预测人类的CD进展。 我们将采用定向和非定向高分辨率质谱学相结合的方法 为了验证这一假设，在玻利维亚CD患者的临床队列中进行了验证。首先，我们将确定是否 将发展为重症和非重症患者的循环酰肉碱谱不同 进步者(目标1)。同时，我们将在相同的血清样本上应用非靶向代谢策略 确定可供选择的生物标志物，并通过准确的质谱定量验证这些生物标志物 在独立样本中(目标2)。共同，目标1和目标2将导致高素质候选人的确定 生物标志物。未来的长期工作将在扩大的临床队列中测试R21中确定的生物标记物 并评估这些生物标记物随时间的变化。总体而言，这项工作满足了巨大的临床需求，通过 为CD确定新的预后生物标志物，这将导致改善患者的管理和治疗。

Project summary/abstract The parasite Trypanosoma cruzi is the causative agent of Chagas disease (CD), which affects 5-6 million people worldwide and over 300,000 in the United States alone. 20% to 30% of T. cruzi-infected individuals develop symptomatic disease leading to heart failure, making it an important cause of heart failure in Latin America. There are currently no tools available for clinicians to predict which patients will develop severe disease and which will not. Standard of care in endemic Latin American nations is to treat all infected children; however, there is no consensus on treatment of asymptomatic adults. Current CDC guidelines recommend treating T. cruzi-positive individuals 50 years or younger who do not yet present severe symptoms; treatment is optional for patients over 50 years old due to the high risk of side effects, even though adults age 51 and over represent a quarter of all CD patients. CD treatment regimens are poorly tolerated, with up to 30% of patients failing to complete the full treatment course due to side effects. Treating all infected individuals exposes the ~70% of T. cruzi-infected individuals who were never going to develop clinical manifestations to a dangerous drug for no reason. An outcome-predictive biomarker would help clinicians and their patients weigh treatment risks and benefits, identify high-risk patients for increased monitoring and follow-up, leading to higher patient compliance and treatment completion, while sparing those who are unlikely to develop heart disease unnecessary drug toxicities. Progression biomarkers would also facilitate clinical trials for novel CD therapeutics. Our recent research has shown that the cardiac small molecule profile differs between severe and mild infections in mice and non-human primates. Key differential metabolites include acylcarnitine family members, which are also decreased by infection in the serum, in chronic CD mouse models. Based on this preliminary data, we hypothesize that serum small molecules will predict CD progression in humans. We will apply a combination of targeted and untargeted high-resolution mass spectrometry-based approaches to test this hypothesis, in a clinical cohort of CD patients from Bolivia. First, we will determine whether the circulating acylcarnitine profile differs between patients who will progress to severe disease and non- progressors (aim 1). In parallel, we will apply an untargeted metabolomic strategy on the same serum samples to identify alternative biomarkers, and validate these biomarkers by accurate mass spectrometric quantification in independent samples (aim 2). Jointly, aims 1 and 2 will lead to the identification of high-quality candidate biomarkers. Future long-term work will test the biomarkers identified in this R21 in expanded clinical cohorts and evaluate how these biomarkers change over time. Overall, this work meets a great clinical need, by identifying new prognostic biomarkers for CD that will lead to improved patient management and treatment.