Small molecule biomarkers of cardiac Chagas disease progression

心脏恰加斯病进展的小分子生物标志物

• 批准号: 10369643
• 负责人: Natalie McCarter Bowman
• 金额: $ 23.5万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-10 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10369643
• 关键词: Address; Adult; Adverse effects; Affect; Age; Animal Model; Antibodies; Antiparasitic Agents; Arrhythmia; Benefits and Risks; Benznidazole; Biological Markers; Bolivia; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Chagas Disease; Child; Cholesterol; Chronic; Clinic; Clinical; Clinical Trials; Cohort Studies; Consensus; Dangerousness; Data; Data Analyses; Detection; Diagnostic Procedure; Dilated Cardiomyopathy; Disease; Disease Progression; Drug Side Effects; Drug toxicity; Early treatment; Effectiveness; Ensure; Evaluation; Family member; Foundations; Future; Goals; Guidelines; Heart Diseases; Heart failure; Human; Individual; Infection; Latin America; Latin American; Lead; Left; Levocarnitine; Liquid Chromatography; Longitudinal Studies; Mass Spectrum Analysis; Medicine; Methods; Monitor; Mus; Neonatal Screening; Outcome; Parasites; Patient Care; Patient Monitoring; Patients; Performance; Persons; Pharmaceutical Preparations; Production; Prognostic Marker; Reaction; Research; Research Personnel; Resolution; Sampling; Serology test; Serum; Severity of illness; Sphingolipids; Symptoms; Testing; Therapeutic; Time; Treatment Protocols; Trypanosoma cruzi; United States; Validation; Ventricular Aneurysm; Weighing patient; Work; acylcarnitine; base; biomarker discovery; candidate marker; chagasic cardiomyopathy; circulating biomarkers; cohort; compliance behavior; disease prognosis; drug development; follow-up; heart damage; high risk; improved; instrumentation; metabolomics; mouse model; nonhuman primate; novel; outcome prediction; oxidation; patient prognosis; predictive marker; progression marker; protein biomarkers; side effect; small molecule; standard of care; success; sudden cardiac death; symptom treatment; tandem mass spectrometry; therapeutic evaluation; tool; treatment response; treatment risk; trimethyloxamine; young woman

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.

项目概要/摘要 寄生虫克氏锥虫是恰加斯病 (CD) 的病原体，影响 5-600 万人 世界各地的人们，仅在美国就有超过 300,000 人。 20% 至 30% 的克氏锥虫感染者 出现导致心力衰竭的症状性疾病，使其成为拉丁语中心力衰竭的重要原因 美国。目前临床医生没有可用的工具来预测哪些患者会发展为重症 疾病，哪些不会。拉丁美洲流行病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尚未达成共识。目前 CDC 指南建议 治疗 50 岁或以下但尚未出现严重症状的克氏锥虫阳性个体；治疗是 由于副作用风险很高，因此对于 50 岁以上的患者来说是可选的，即使是 51 岁及以上的成年人 占所有 CD 患者的四分之一。 CD 治疗方案的耐受性很差，高达 30% 的患者 由于副作用而未能完成整个疗程。治疗所有感染者暴露了 约 70% 的克氏锥虫感染者永远不会出现危险的临床表现 无缘由地吸毒。结果预测生物标志物将帮助临床医生及其患者权衡治疗 风险和收益，识别高风险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。进展生物标志物也将促进新型 CD 的临床试验 疗法。我们最近的研究表明，严重的心脏小分子谱存在差异 以及小鼠和非人类灵长类动物的轻度感染。主要差异代谢物包括酰基肉碱家族 在慢性 CD 小鼠模型中，这些成员也因血清感染而减少。基于此 根据初步数据，我们假设血清小分子将预测人类 CD 的进展。 我们将结合使用靶向和非靶向高分辨率质谱方法 为了检验这一假设，我们在玻利维亚的 CD 患者临床队列中进行了研究。首先，我们要确定是否 将进展为严重疾病的患者和非疾病患者之间的循环酰基肉碱谱有所不同 进步者（目标 1）。同时，我们将对相同的血清样本应用非靶向代谢组学策略 识别替代生物标志物，并通过精确的质谱定量验证这些生物标志物 在独立样本中（目标 2）。目标 1 和 2 将共同确定高质量的候选人 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 中确定的生物标志物 并评估这些生物标志物如何随时间变化。总的来说，这项工作满足了很大的临床需求， 确定新的 CD 预后生物标志物，这将改善患者的管理和治疗。

项目成果

Persistent biofluid small molecule alterations induced by Trypanosoma cruzi infection are not restored by antiparasitic treatment.

抗寄生虫治疗无法恢复由克氏锥虫感染引起的持续性生物流体小分子改变。

• DOI: 10.1101/2023.06.03.543565
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Dean,DanyaA;Roach,Jarrod;vonBargen,RebeccaUlrich;Xiong,Yi;Kane,ShelleyS;Klechka,London;Wheeler,Kate;Sandoval,MichaelJimenez;Lesani,Mahbobeh;Hossain,Ekram;Katemauswa,Mitchelle;Schaefer,Miranda;Harris,Morgan;Barron,Sayre;Liu,
• 通讯作者: Liu,

Molecular networking in infectious disease models.

• DOI: 10.1016/bs.mie.2021.09.018
• 发表时间: 2022
• 期刊: Methods in enzymology