Mechanisms of eosinophil-associated heart disease

项目摘要 20-60%的外周血嗜酸性粒细胞增多症患者发生心脏并发症， 原因-嗜酸性粒细胞增多综合征（HES），嗜酸性肉芽肿性多血管炎 (EGPA以前称为Churg-Strauss综合征）、药物反应或寄生虫感染。重要的是， 心脏病是这一不同患者群体发病率和死亡率的主要原因。有一个 缺乏充分复制嗜酸性粒细胞增多症中心脏疾病的模型，这阻碍了 机制研究，将确定治疗目标和推进临床实践。解决 我们最近开发了一种小鼠嗜酸性心肌炎模型， 该疾病的特征包括嗜酸性粒细胞增多并累及心脏，导致早期死亡。我们 长期的目标是了解嗜酸性粒细胞介导的组织的细胞和分子机制， 损害这项资助的目的是使用这种小鼠模型来解决关键问题， 嗜酸性粒细胞介导的心脏病的病理生理学。我们的核心假设是嗜酸性粒细胞 并且特定类型的嗜酸性细胞死亡在嗜酸性心肌炎中具有致病作用。我们 提出了两个具体的目标：1）确定嗜酸性粒细胞的作用和他们的调节性坏死，嗜酸性粒细胞 心肌炎;和2）测试的证据，调节坏死和抗嗜酸性粒细胞自身抗体， 嗜酸性粒细胞相关疾病患者。这些贡献是重要的，因为心脏 疾病是嗜酸性粒细胞增多症患者发病和死亡的主要原因; 在这项赠款申请的研究将能够直接测试在一个模型中的机制假设， 嗜酸性粒细胞性心肌炎，其特征使人联想到心脏病患者， 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 假设，包括最近描述的生物化学调节模式的作用， 靶向嗜酸性粒细胞死亡。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在一个 高嗜酸性粒细胞设置将提供机制的见解，可能是推广到其他条件 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.