Targeting purinergic signaling in Chagas disease
靶向恰加斯病中的嘌呤能信号传导
基本信息
- 批准号:10662905
- 负责人:
- 金额:$ 13.07万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdenosineArgentinaBenznidazoleBiologyCardiacCardiac MyocytesCardiomyopathiesCell DensityCell LineageCell SeparationCellsCellular ImmunityChagas DiseaseChagas MyocarditisChronicCicatrixComplicationConsumptionCountryDevelopmentDisease ProgressionDrug Delivery SystemsDrug KineticsEnvironmentEquilibriumEtiologyExperimental ModelsFosteringFrequenciesGene ExpressionGrowthHeartHeart failureHumanHypoxiaImmuneImmune responseImmunityImmunohistochemistryInfectionInflammatory ResponseInterventionInvestigationIschemiaKnowledgeLatin AmericaLesionLeukocytesLinkMacrophageModelingMovementMusMyeloid CellsMyocarditisNucleosidesOutcomeOxygenParasitesParticulatePathogenesisPathogenicityPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsPopulationPreventive vaccinePublic HealthPurinoceptorRegulatory PathwayReportingRoleSignal PathwaySignal TransductionSterilityStrokeSudden DeathSystemT-LymphocyteTestingTimeTissuesTransplant RecipientsTreatment EfficacyTrypanosoma cruziVaccine TherapyValidationaffectionchagasic cardiomyopathychemotherapyclinically relevantextracellularimmunopathologyimmunoregulationimprovedinflammatory milieuinsightmicrobicidemouse modelnovelnovel strategiespathogenpharmacologicresponseside effect
项目摘要
Project Summary
Chagas disease, a major public health problem in Latin America, is caused by the infection with the protozoan
parasite Trypanosoma (T.) cruzi and has been spread to non-endemic regions by migratory movements. Chagas
cardiomyopathy represents the most severe complication of chronic Chagas disease in Argentina. This important
illness has become a frequent cause of heart failure, cardio-embolic stroke, and sudden death in our and other
endemic countries. There are still no effective prophylactic vaccines, and chemotherapy mainly relies on
benznidazole, a 60-year-old drug linked to prolonged treatment and significant side effects. This parasite is an
obligate intracellular pathogen that can infect any nucleated cell, but the clinically relevant niches are the
cardiomyocytes since the parasite remains in the heart for several decades before the development of the
cardiomyopathy. Therefore, one of the main challenges in understanding Chagas disease immunopathology is
to find out why the parasite is not completely eliminated, being able to sustain a pathological inflammatory
environment. After infection, the influx of immune cells consumes large amounts of oxygen, and ischemic cells
rapidly respond to the hypoxic and inflammatory environment by releasing ATP to the extracellular milieu. This
extracellular ATP (eATP) triggers microbicidal immune responses but is quickly hydrolyzed to the potent
immunosuppressive metabolite adenosine, mainly via the concerted activity of CD39 and CD73 ectoenzymes.
Increasing evidence suggests that the balance of purinergic signaling determines the immune response's
outcome in different pathological scenarios. We hypothesize that the balance of purinergic responses to eATP
and the nucleosides generated by CD39 and CD73 determines anti-T. cruzi immunity and triggers pathogenic
mechanisms in Chagas disease. Hence, manipulating these signaling pathways could provide new approaches
to limiting cardiac pathology. The central hypothesis will be tested by pursuing three specific aims: 1) Validate
the participation of purinergic signaling in the cardiac response to T. cruzi infection in advanced human Chagas
disease, 2) Determine the impact of CD39-CD73 ectoenzymes on the cellular immune response, and the
progression of Chagas cardiomyopathy by employing experimental murine models, 3) Explore the benefits of
pharmacological targeting of purinergic signaling in a mouse model of Chagas cardiomyopathy. These
investigations will provide a comprehensive understanding of crucial mechanisms through which T. cruzi
infection subverts immune response to sustain parasite persistence and a detailed insight into the biology of the
cardiac response to infection.
1
项目摘要
南美锥虫病是拉丁美洲的一个主要公共卫生问题,
寄生虫锥虫(T.)cruzi,并已通过移徙运动传播到非流行地区。恰加斯
心肌病是阿根廷慢性恰加斯病最严重的并发症。这一重要
疾病已经成为我们和其他人心力衰竭、心源性栓塞性中风和猝死的常见原因
流行国家。目前还没有有效的预防性疫苗,化疗主要依靠
苯并咪唑,一种有60年历史的药物,与长期治疗和显著的副作用有关。这种寄生虫是
专性细胞内病原体,可以感染任何有核细胞,但临床相关的小生境是
由于寄生虫在心肌细胞发育之前在心脏中存在数十年,
心肌病因此,理解恰加斯病免疫病理学的主要挑战之一是
找出为什么寄生虫没有完全消除,能够维持病理性炎症,
环境感染后,免疫细胞的涌入消耗了大量的氧气,
通过向细胞外环境释放ATP快速响应缺氧和炎症环境。这
细胞外ATP(eATP)触发杀微生物免疫反应,但很快被水解为有效的
免疫抑制代谢物腺苷,主要通过协同活性的CD 39和CD 73胞外酶。
越来越多的证据表明,嘌呤能信号的平衡决定了免疫反应的
在不同的病理情况下。我们推测eATP的嘌呤能反应平衡
由CD 39和CD 73产生的核苷决定抗T细胞。cruzi免疫和触发致病
恰加斯病的发病机制因此,操纵这些信号通路可以提供新的方法,
限制心脏病理学。中心假设将通过追求三个具体目标来检验:1)
嘌呤能信号通路参与T.晚期人类南美锥虫的克氏感染
2)确定CD 39-CD 73胞外酶对细胞免疫应答的影响,以及
通过采用实验小鼠模型研究查加斯心肌病的进展,3)探索
在查加斯心肌病小鼠模型中嘌呤能信号传导的药理学靶向。这些
调查将提供一个全面的了解的关键机制,通过T。cruzi
感染破坏免疫反应,以维持寄生虫的持久性,并详细了解
心脏对感染的反应
1
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Maria Pilar Aoki其他文献
A novel mouse model for studying complications related to type 2 diabetes using a medium-fat diet, fructose, and streptozotocin
一种利用中脂肪饮食、果糖和链脲佐菌素研究与 2 型糖尿病相关并发症的新型小鼠模型
- DOI:
10.1038/s41598-025-04335-3 - 发表时间:
2025-07-01 - 期刊:
- 影响因子:3.900
- 作者:
Yanina Luciana Mazzocco;Gastón Bergero;Sebastian Del Rosso;Zoé Magalí Cejas Gallardo;Alejandra Mariel Canalis;Ruth Eliana Baigorri;Luciana Mezzano;Juan Javier Mladin;Gustavo Tomás Díaz-Gerevini;Claudia Martínez Benavidez;Roxana Carolina Cano;Maria Pilar Aoki - 通讯作者:
Maria Pilar Aoki
Maria Pilar Aoki的其他文献
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