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.
慢性克氏锥虫感染引起心肌炎和进行性心脏纤维化的机制
项目成果
期刊论文数量(0)
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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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