Mechanisms of myocarditis and progressive cardiac fibrosis in chronic Trypanosoma cruzi infection.
慢性克氏锥虫感染心肌炎和进行性心脏纤维化的机制。
基本信息
- 批准号:10594507
- 负责人:
- 金额:$ 78.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-18 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AddressAdjuvantAffectAgonistAntigensAntiparasitic AgentsBenznidazoleCD8-Positive T-LymphocytesCardiacCardiac healthCellsChagas DiseaseChronicClinicalCollagenCombined Modality TherapyComplexDataDepositionDevelopmentDiseaseDisease ProgressionDoseEchocardiographyElectrocardiogramEmulsionsFailureFibrosisGoalsHeartHeart failureImaging TechniquesImmune responseImmunotherapyInfectionInfiltrationInflammationInflammatoryInflammatory ResponseInterventionKnowledgeLinkLiver FibrosisMeasuresMetabolicMetabolic PathwayMetabolic dysfunctionMusMyocardial dysfunctionMyocarditisNeuropathyOrgan PreservationOutcomeParasitesPathogenesisPathologyPathway interactionsPatient-Focused OutcomesPatientsPersonsPhosphorylationPlatelet-Derived Growth FactorProteinsProtozoaPulmonary FibrosisRecombinantsSTAT1 geneSTAT3 geneSchemeSeveritiesSeverity of illnessSignal TransductionSudden DeathTLR4 geneTNF geneTherapeutic InterventionTimeTissuesTransforming Growth Factor betaTrypanosoma cruziTyrosine PhosphorylationVaccinesVascular DiseasesWorkacylcarnitinechagasic cardiomyopathychemotherapychronic infectionconnective tissue growth factorcoronary fibrosiscytokineefficacy evaluationheart functionheart imagingheart metabolismheart preservationimprovedinflammatory markerintervention effectmouse modelparasite invasionresponseskin fibrosissmall moleculesynergismtargeted treatmenttreatment strategyvector-borne
项目摘要
Mechanisms of myocarditis and progressive cardiac fibrosis in chronic Trypanosoma cruzi infection
Abstract:
Chagas disease, caused by infection with the vector borne intracellular protozoal parasite Trypanosoma cruzi,
affects approximately 6.5 million people worldwide. Chronic infection with T. cruzi results in persistent low grade
myocarditis and progressive fibrosis, which results in significant cardiac dysfunction called Chronic Chagasic
Cardiomyopathy (CCC). Patients with CCC have higher levels of cardiac inflammation, fibrosis, and circulating
inflammatory and fibrotic markers that correlate with disease severity. The antiparasitic drug benznidazole fails
to ameliorate the chronic inflammation and progressive fibrosis of CCC. Our long term goal is to define the
mechanisms of host inflammation, fibrosis and metabolic dysregulation in CCC in an effort to identify targets for
therapeutic interventions. T. cruzi induces host inflammatory and fibrotic pathways through multiple mechanisms.
Based on our knowledge of these mechanisms, we developed an immunotherapy consisting of the T. cruzi
derived antigen Tc24-C4 and a TLR4 agonist adjuvant. We previously showed that the immunotherapy, either
alone or combined with benznidazole in a vaccine-linked chemotherapy strategy, modulates host inflammatory
immune responses and results in reduced myocarditis and fibrosis. Additionally, we have shown that similar to
mouse models of lung, skin and liver fibrosis, inhibiting STAT3 activation with the small molecule TTI-101
significantly reduces cardiac fibrosis in a mouse model of CCC. This work led to our central hypothesis that
targeting host inflammatory and fibrotic pathways will synergize with anti-parasitic treatment to reduce cardiac
inflammation and fibrosis and improve cardiac health in CCC. Building on our preliminary data, we propose three
Specific Aims to evaluate efficacy of this combined treatment scheme: 1) Determine the effect of targeted
interventions (immunotherapy, benznidazole and TTI-101) on modulating parasite-induced inflammatory
immune responses; 2) Determine the effect of targeted interventions on modulating parasite-induced pro-fibrotic
response; and 3) Determine the effect of targeted interventions on modulating parasite-induced metabolic
responses. Through these aims, we will better define the pathogenesis of CCC, specifically the relative
contribution of host inflammatory, fibrotic, and metabolic dysregulation to disease progression. Targeted
interventions that restore the inflammatory, fibrotic and metabolic pathways to normal, and preserve cardiac
health, will help us identify key host response mechanisms that contribute to CCC. Additionally, these studies
will provide important proof of concept for developing multi-modal treatment strategies that target both the
parasite and underlying tissue pathologies of CCC to preserve cardiac health and ultimately improve clinical
outcomes.
慢性克氏锥虫感染致心肌炎和进行性心脏纤维化的机制
摘要:
查加斯病,由携带细胞内原生动物寄生虫克氏锥虫的载体感染引起,
影响了全世界约650万人。慢性感染T.克鲁济指数持续偏低
心肌炎和进行性纤维化,导致严重的心脏功能障碍,称为慢性胆固醇血症
心肌病(CCC)。CCC患者的心脏炎症、纤维化和循环系统疾病水平较高,
与疾病严重程度相关的炎症和纤维化标志物。抗寄生虫药苄硝哒唑
改善CCC的慢性炎症和进行性纤维化。我们的长期目标是定义
CCC中宿主炎症、纤维化和代谢失调的机制,以确定CCC的靶点。
治疗干预。T. Cruzi通过多种机制诱导宿主炎症和纤维化途径。
基于我们对这些机制的了解,我们开发了一种由T。cruzi
衍生抗原Tc 24-C4和TLR 4激动剂佐剂。我们之前的研究表明,
单独或与苄硝唑联合使用,可调节宿主炎症反应,
免疫反应,并导致减少心肌炎和纤维化。此外,我们还表明,类似于
肺、皮肤和肝纤维化的小鼠模型,用小分子TTI-101抑制STAT 3活化
显著降低CCC小鼠模型中的心脏纤维化。这项工作导致了我们的中心假设,
靶向宿主炎症和纤维化途径将与抗寄生虫治疗协同作用,
炎症和纤维化并改善CCC心脏健康。根据我们的初步数据,我们提出三个
评价该联合治疗方案的疗效的具体目的:1)确定靶向治疗的效果。
干预措施(免疫疗法、苄硝唑和TTI-101)对调节寄生虫诱导的炎症
2)确定靶向干预对调节寄生虫诱导的促纤维化的作用
3)确定靶向干预对调节寄生虫诱导的代谢的影响
应答通过这些目标,我们将更好地定义CCC的发病机制,特别是相对于
宿主炎症、纤维化和代谢失调对疾病进展的贡献。针对性
使炎症、纤维化和代谢途径恢复正常,
健康,将帮助我们确定关键的主机响应机制,有助于CCC。此外,这些研究
将为开发多模式治疗策略提供重要的概念证明,
寄生虫和CCC的基础组织病理学,以保护心脏健康并最终改善临床
结果。
项目成果
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Kathryn Marie Jones其他文献
Kathryn Marie Jones的其他文献
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{{ truncateString('Kathryn Marie Jones', 18)}}的其他基金
Mechanisms of myocarditis and progressive cardiac fibrosis in chronic Trypanosoma cruzi infection.
慢性克氏锥虫感染心肌炎和进行性心脏纤维化的机制。
- 批准号:
10421179 - 财政年份:2022
- 资助金额:
$ 78.52万 - 项目类别:
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