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 寄生虫克氏锥虫是南美锥虫病（CD）的病原体，影响5-6百万人 全世界的人，仅在美国就有超过30万人。20%~ 30%的T.克氏病感染者 发展导致心力衰竭的症状性疾病，使其成为拉丁语心力衰竭的重要原因 美国参考目前临床医生还没有工具可以预测哪些患者会发展为严重的 病，哪些不会。流行病拉丁美洲国家的护理标准是治疗所有受感染的儿童; 然而，对无症状成人的治疗没有共识。目前CDC指南建议 治疗T. 50岁或50岁以下尚未出现严重症状的cruzi阳性个体;治疗是 50岁以上的患者可选，因为副作用的风险高，即使是51岁及以上的成年人 占所有CD患者的四分之一CD治疗方案耐受性差，高达30%的患者 由于副作用而无法完成整个疗程。治疗所有受感染的个体暴露了 ~70%的T.那些从未有过临床表现的克鲁兹感染者， 药物没有理由。结果预测生物标志物将帮助临床医生和他们的患者权衡治疗 风险和受益，识别高风险患者以增加监测和随访，导致患者 依从性和治疗完成，同时保留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 治疗学我们最近的研究表明，心脏小分子谱在严重的 以及小鼠和非人类灵长类动物的轻度感染。关键差异代谢物包括酰基肉毒碱家族 在慢性CD小鼠模型中，其也通过血清中的感染而降低。基于此 根据初步数据，我们假设血清小分子可以预测人类CD的进展。 我们将应用靶向和非靶向高分辨率质谱法为基础的方法相结合 为了验证这一假设，在来自玻利维亚的CD患者的临床队列中。首先，我们将确定 循环酰基肉毒碱谱在将进展为严重疾病的患者和非严重疾病的患者之间存在差异。 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 鉴定替代生物标志物，并通过准确的质谱定量验证这些生物标志物 独立样本（目标2）。目标1和目标2将共同导致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本R21中鉴定的生物标志物 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，将改善患者管理和治疗。

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