Identification and Assessment of Surrogate Biomarkers for Chronic Chagas Disease

慢性恰加斯病替代生物标志物的鉴定和评估

• 批准号: 8304506
• 负责人: EDECIO CUNHA-NETO
• 金额: $ 0.38万
• 依托单位: FUNDACAO FACULDADE DE MEDICINA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8304506
• 关键词: Adult; Adverse effects; Affect; Animal Model; Antibodies; Benznidazole; Biological Assay; Biological Markers; Blood; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Chagas Disease; Chronic; Classification; Clinical; Clinical Management; Clinical Trials; Communicable Diseases; Consent; DNA; Data; Disease; Disease Progression; Evaluation; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Heart Diseases; Immune; Immune Targeting; Immune response; Immune system; Immunologic Markers; Infection; Inflammation; Inflammatory; Inflammatory Response; Lead; Leukocytes; Life; Measures; Messenger RNA; Monitor; Organ; Outcome; Parasites; Patient Representative; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Plasma Proteins; Predictive Value; Problem Solving; Research; Sampling; Staging; Testing; Therapeutic; Time; Tropical Disease; Trypanocidal Agents; Trypanosoma cruzi; Whole Blood; base; cohort; experience; improved; neglect; outcome forecast; parasitism; peripheral blood; prognostic; response

Although low-grade parasite persistence is a fundamental aspect of chronic Chagas disease, current parasitological assays have low sensitivity and are not quantitative. Benznidazole, the only available trypanocidal drug, has questionable efficacy in the treatment of chronic Chagas disease patients. There is an urgent need to perform clinical trials of new drugs for chronic Chagas disease, however the lack of reliable biomarkers for reduction of parasitism and consequent inflammatory responses and damage is a major obstacle for evaluating new drugs. The identification of differentiating markers for presence and levels of 7. crtvz; parasitism and resulting immune and inflammatory perturbations could potentially solve this problem. The few available biomarkers for parasitism and disease progression are neither quantitative nor highly predictive. It is known that composite biomarkers have a higher potential for differentiating clinical outcomes than single markers. Blood gene expression profiling has been used to differentiate between patients with distinct courses of infection in several infectious diseases including preliminary data from our group for Chagas disease. We hypothesize that persistent parasitism by 7. cruzi, induces specific changes in PBMC gene expression patterns. A second hypothesis is that distinct stages of infection, defined based on clinical presentation and findings and 7. cruzi PCR and antibody results, will display specific composite biomarker profiles. The major aims of this project are to identify the transcriptional profiles of high and low 7. cruzi parasitism as well as the transcriptional profiles of patients with different clinical presentations, and to combine the findings from transcriptome analyses with other biomarker parameters we are currently characterizing. The study will evaluate a sample of patients representative of distinct clinical stages of Chagas disease and intensity of parasitism (as measured by 7. cruzi real-time PCR), along with seronegative controls, from the REDS II Chagas cohort. Transcriptome analysis of whole blood will be performed, and transcriptional signatures that correlate with each clinical group will be validated with qPCR assays that can be applied to larger sample sets. We will then test the classifying ability of validated mRNA markers on the remainder of the REDS II Chagas disease cohort (600 patients and 100 seronegative controls). Plasma protein biomarkers of inflammation and cardiovascular disease and 7. cruz/antibody profiles/titers, which are being characterized in the same patient groups, will be combined with transcriptome signatures to construct an improved composite biomarker profile for prognosis and therapeutic monitoring.

虽然低度寄生虫持续存在是慢性恰加斯病的一个基本方面，但目前的寄生虫学检测灵敏度低，而且不能定量。苯硝咪唑是唯一可用的杀锥虫药物，在治疗慢性恰加斯病患者方面的疗效值得怀疑。目前迫切需要对慢性恰加斯病的新药进行临床试验，然而，缺乏可靠的生物标志物来减少寄生虫和随之而来的炎症反应和损伤是评估新药的主要障碍。鉴别的存在和水平的分化标记7。CRTVZ;寄生和由此产生的免疫和炎症扰动可能潜在地解决这个问题。少数可用的寄生虫和疾病进展的生物标志物既不是定量的，也不是高度预测的。已知复合生物标志物比单一标志物具有更高的区分临床结果的潜力。血液基因表达谱已被用于区分几种传染病中具有不同感染过程的患者，包括来自我们查加斯病小组的初步数据。我们假设持续寄生7。cruzi诱导PBMC基因表达模式的特异性变化。第二个假设是不同阶段的感染，根据临床表现和发现定义，7。cruzi PCR和抗体结果将显示特定的复合生物标志物谱。该项目的主要目的是确定高和低7的转录谱。cruzi寄生以及具有不同临床表现的患者的转录谱，并且将来自转录组分析的结果与我们目前表征的其他生物标志物参数联合收割机结合。该研究将评估代表查加斯病不同临床阶段和寄生虫强度的患者样本（如通过7. cruzi实时PCR），沿着血清阴性对照，来自REDS II查加斯病群组。将对全血进行转录组分析，并使用可应用于较大样本集的qPCR检测试剂盒验证与每个临床组相关的转录特征。然后，我们将测试经验证的mRNA标记物对REDS II恰加斯病队列的其余部分（600名患者和100名血清阴性对照）的分类能力。炎症和心血管疾病的血浆蛋白生物标志物和7.将在相同患者组中表征的Cruz/抗体谱/滴度与转录组标记组合以构建用于预后和治疗监测的改进的复合生物标志谱。