Pathogenesis of autoimmune valvular carditis

自身免疫性瓣膜性心脏病的发病机制

基本信息

批准号：
10624894
负责人：
Bryce Binstadt
金额：
$ 37.66万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10624894
关键词：
Acceleration Affect Anti-Inflammatory Agents Antiphospholipid Syndrome Aorta Atherosclerosis Autoantibodies Autoimmune Autoimmune Diseases Automobile Driving Award Biophysics Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Carditis Cause of Death Cell Communication Cell Lineage Cells Cessation of life Chronic Data Disease Endothelial Cells Endothelium Fc Receptor Fibroblasts Fibrosis Gene Expression Gene Expression Profile Genes Genetic Transcription Goals Heart Heart Valve Diseases Heart Valves Human Immune Immune response Immune system Immunity Inflammation Inflammatory Inflammatory Arthritis Interleukin-1 Interleukin-13 Interleukin-4 Knowledge Lead Left Link Lupus Lymphoid Cell Macrophage Macrophage Activation Mediating Mediator Mesenchymal Mitral Valve Modeling Molecular Morbidity - disease rate Mus Myeloid Cells Myofibroblast Normal Cell Oxygen Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patient-Focused Outcomes Patients Persons Piezo 1 ion channel Population Predisposition Process Production Proteins Research Rheumatic Fever Rheumatic Heart Disease Rheumatism Rheumatoid Arthritis Role Side Study models System Therapeutic Tissues Tricuspid valve structure antifibrotic treatment atherosclerosis risk autoimmune arthritis autoimmune pathogenesis cardiovascular disorder risk cell type cytokine differential expression disorder subtype experimental study high risk improved improved outcome insight interleukin-13 receptor interstitial cell mechanotransduction mitral cell mortality mouse model novel phase III trial progenitor programs receptor shear stress success transcriptome virtual

项目摘要

Abstract Patients with chronic inflammatory/rheumatic diseases suffer increased cardiovascular morbidity and mortality. Improving outcomes requires understanding how chronic inflammation causes cardiovascular pathology. The focus of this proposal is on valvular carditis. The most common cause of valvular carditis is rheumatic heart disease (RHD), which affects >30 million people worldwide and causes >300,000 deaths annually. Valvular carditis also occurs in patients with lupus and the related antiphospholipid antibody syndrome. Our group has pioneered a mouse model of co-existing valvular carditis and inflammatory arthritis, with pathologic features recapitulating those in human patients. Our group was the first to show a critical role for myeloid cells in promoting valvular carditis. Specifically, we showed that autoantibodies engage particular Fc receptors on macrophages, leading to pro-inflammatory cytokine production and macrophage polarization, leading to chronic valve inflammation and fibrosis. We have identified the cytokine interleukin-13 (IL-13) as a key driver of this process. The current proposal builds on these findings and extends them. Here we will identify the cell type producing IL-13; preliminary data suggest type 2 innate lymphoid cells (ILC2s). We will also identify the pathways that lead to increased IL-13 production, focused on cytokines made by endothelial cells. Type 2 immune responses are known to promote tissue fibrosis, which occurs in the cardiac valves of patients with RHD and in our mouse model, characterized by the presence of myofibroblasts in the valves. The cell from which these myofibroblasts originate is not known. We propose sophisticated cell lineage tracing experiments to identify myofibroblast progenitors among valve interstitial cells (VICs) in valvular carditis. Understanding the origin of the myofibroblasts is critical to targeting them therapeutically. Finally, we are focused on the puzzling question of why valvular carditis preferentially affects the left-sided heart valves (mitral and aortic) and not the right-sided ones – this is true in both human patients and the mouse model. Many possibilities exist. Our preliminary data show that the expression of key genes and proteins involved in type 2 immunity or in sensing biophysical variables (e.g. oxygen tension and shear stress) differs between the left- and right-sided valves in normal mice. We therefore propose to perform comprehensive analysis of cardiac valve gene expression to identify molecular pathways that underlie this left-sided predilection. Guided by these data, we will interrogate the most promising of these pathways. In sum, we will define how discrete populations of immune cells interact with endothelial cells and VICs to cause chronic valve inflammation and fibrosis. Further, we will reveal why the milieu of the left side of the heart promotes inflammation and fibrosis. Although we are focused here on valvular carditis, we expect that our findings will be generalizable to other types of cardiovascular inflammation, including atherosclerosis.

抽象的患有慢性炎症/风湿性疾病的患者心血管发病率和死亡率增加。改善结果需要了解慢性炎症如何导致心血管病理。该提案的重点是瓣膜性心脏炎瓣膜性心脏炎最常见的原因是风湿性心脏。疾病（RHD），影响全球超过 3000 万人，每年导致超过 30 万人死亡。狼疮患者和相关的抗磷脂抗体综合征患者也会出现心脏炎。首创了心脏瓣膜炎和炎症性关节炎共存的小鼠模型，具有病理特征我们的研究小组是第一个在人类患者中展示骨髓细胞的关键作用的研究小组。具体来说，我们发现自身抗体与特定的 Fc 受体结合。巨噬细胞，导致促炎细胞因子的产生和巨噬细胞极化，导致我们已确定细胞因子白细胞介素 13 (IL-13) 是慢性瓣膜炎症和纤维化的关键驱动因素。当前的提案建立在这些发现的基础上并对其进行扩展，在这里我们将识别细胞类型。产生 IL-13；初步数据表明 2 型先天淋巴细胞 (ILC2)。导致 IL-13 产生增加的途径，重点关注 2 型内皮细胞产生的细胞因子。众所周知，免疫反应会促进组织纤维化，这种纤维化发生在患有以下疾病的患者的心脏瓣膜中： RHD 和我们的小鼠模型中，其特征是瓣膜中存在肌成纤维细胞。这些肌成纤维细胞的来源尚不清楚，我们提出了复杂的细胞谱系追踪实验。鉴定瓣膜间质细胞（VIC）中的肌纤维母细胞祖细胞。肌成纤维细胞的起源对于靶向治疗至关重要。最后，我们关注的是令人困惑的问题。为什么瓣膜性心脏炎优先影响左侧心脏瓣膜（二尖瓣和主动脉）而不是左侧心脏瓣膜？右侧的——这在人类患者和小鼠模型中都存在。初步数据表明，参与2型免疫或传感的关键基因和蛋白质的表达左侧和右侧瓣膜的生物物理变量（例如氧张力和剪切应力）不同因此，我们建议对正常小鼠的心脏瓣膜基因表达进行全面分析。在这些数据的指导下，我们将探究导致这种左侧偏爱的分子途径。总之，我们将定义离散的免疫细胞群体如何相互作用。内皮细胞和 VIC 会导致慢性瓣膜炎症和纤维化。此外，我们将揭示原因。尽管我们在这里关注的是心脏左侧的环境会促进炎症和纤维化。瓣膜性心脏炎，我们希望我们的研究结果能够推广到其他类型的心血管炎症，包括动脉粥样硬化。