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

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.
慢性克氏锥虫感染心肌炎和进展性心肌纤维化的机制 摘要: 查加斯病,由媒介传播的细胞内原生动物寄生虫克氏锥虫感染引起, 影响全球约650万人。慢性感染克鲁兹毛滴虫导致持续低级别 心肌炎和进行性纤维化,导致严重的心脏功能障碍,称为慢性心力衰竭 心肌病(CCC)。CCC患者的心脏炎症、纤维化和循环水平较高。 与疾病严重程度相关的炎症和纤维化标志物。抗寄生虫药苯硝唑失败 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 慢性阻塞性肺疾病宿主炎症、纤维化和代谢失调的机制,以努力确定靶点 治疗性干预。克鲁兹毛滴虫通过多种机制诱导宿主炎症和纤维化。 基于我们对这些机制的了解,我们开发了一种由克氏支原体组成的免疫疗法。 衍生抗原Tc24-C4和TLR4激动剂佐剂。我们之前的研究表明,免疫疗法 在疫苗相关的化疗策略中,单独或与苯硝唑联合使用,调节宿主炎症 免疫反应和结果减少心肌炎和纤维化。此外,我们还展示了类似于 小分子TTI-101抑制STAT3活化的小鼠肺、皮肤和肝纤维化模型 显著减少慢性阻塞性肺疾病小鼠的心脏纤维化。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以减少心脏 炎症和纤维化,并改善心脏健康。基于我们的初步数据,我们提出了三个 具体目的是评价本综合治疗方案的疗效:1)确定靶向治疗效果 干预措施(免疫疗法、苯硝唑和TTI-101)对寄生虫诱导的炎症的调节 免疫反应;2)确定靶向干预在调节寄生虫诱导的促纤维化中的作用 响应;以及3)确定靶向干预在调节寄生虫诱导的代谢方面的效果 回应。通过这些目标,我们将更好地定义CCC的发病机制,特别是相关的 宿主炎症、纤维化和代谢失调在疾病进展中的作用。目标明确 使炎症、纤维化和代谢途径恢复正常并保护心脏的干预措施 健康,将帮助我们确定有助于CCC的关键宿主反应机制。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,这些策略针对 保护心脏健康并最终改善临床的CCC的寄生虫和潜在的组织病理学 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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