Mechanisms of eosinophil-associated heart disease

项目总结 心脏并发症发生在20%-60%的外周血高嗜酸性粒细胞增多症患者中 病因--嗜酸性粒细胞增多综合征(HES)、嗜酸性肉芽肿合并多血管炎 (EGPA，以前称为丘格施特劳斯综合征)、药物反应或寄生虫感染。重要的是 心脏病是导致这类不同患者发病和死亡的主要原因。有一个 缺乏在高嗜酸性粒细胞增多症中充分复制心脏病的模型，这阻碍了 将确定治疗靶点并推进临床实践的机械性研究。致信地址 这个缺口，我们最近开发了一种嗜酸性心肌炎的小鼠模型，它概括了许多 该病的特点包括嗜酸性粒细胞增多症，并伴有心脏受累，导致早期死亡。我们的 长期目标是了解嗜酸性粒细胞介导的组织的细胞和分子机制。 损坏。这项资助的目标是使用这种鼠标模型来解决以下关键问题 嗜酸性粒细胞介导的心脏病的病理生理学。我们的中心假设是嗜酸性粒细胞 特殊类型的嗜酸性细胞死亡在嗜酸性心肌炎中起致病作用。我们 提出两个具体目标：1)确定嗜酸性粒细胞及其调节的坏死在嗜酸性粒细胞中的作用 心肌炎；以及2)检测调节性坏死和抗嗜酸性粒细胞自身抗体在 患有嗜酸性粒细胞相关疾病的患者。这些贡献是重大的，因为心 疾病是高嗜酸性粒细胞疾病患者发病和死亡的主要原因； 这项拨款申请的研究将能够在一个模型中直接测试机械假说 嗜酸性心肌炎，其特征使人联想到心脏病患者的 高嗜酸性粒细胞增多症的后果。这个项目是创新的，因为它提出了测试创新 假说，包括最近描述的一种生化调控模式的作用，因此 有针对性的嗜酸性粒细胞死亡。此外，这种方法是创新的，因为我们使用了一种新的鼠标 自发性嗜酸性心肌炎模型。了解更多关于心脏病的知识 高嗜酸性粒细胞环境将提供可推广到其他情况的机械性见解 嗜酸性粒细胞相关的心脏病。

PROJECT SUMMARY Cardiac complications occur in 20-60% of patients with peripheral blood hypereosinophilia irrespective of the cause—hypereosinophilic syndrome (HES), eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), drug reaction, or parasitic infection. Importantly, heart disease is the main cause of morbidity and mortality in this diverse group of patients. There is a paucity of models that adequately replicate cardiac disease in hypereosinophilia, which hinders mechanistic research that would identify therapeutic targets and advance clinical practice. To address this gap, we recently developed a mouse model of eosinophilic myocarditis that recapitulates many of the features of the disease including eosinophilia with heart involvement leading to early death. Our long-term goal is to understand the cellular and molecular mechanisms of eosinophil-mediated tissue damage. The objective of this grant is to use this mouse model to address critical questions regarding the pathophysiology of eosinophil-mediated cardiac disease. Our central hypothesis is that eosinophils and specific types of eosinophil cell death have a pathogenic role in eosinophilic myocarditis. We propose two specific aims: 1) define the role of eosinophils and their regulated necrosis in eosinophilic myocarditis; and 2) test for evidence of regulated necrosis and anti-eosinophil autoantibodies in patients with eosinophil-associated diseases. These contributions are significant because heart disease is the major cause of morbidity and mortality in patients with hypereosinophilic diseases; the studies in this grant application will enable directly testing mechanistic hypotheses in a model of eosinophilic myocarditis with features reminiscent of those seen in patients with heart disease as a consequence of hypereosinophilia. This project is innovative because it proposes to test innovative hypotheses, including the role of a recently described mode of biochemically regulated and thus targetable eosinophil cell death. Furthermore, the approach is innovative in that we use a new mouse model of spontaneous eosinophilic myocarditis. Understanding more about cardiac disease in a hypereosinophilic setting will provide mechanistic insights that may be generalizable to other conditions of eosinophil-associated heart disease.