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.

抽象的慢性炎症/风湿病患者的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引起心血管病理。这该建议的重点是瓣膜性心脏炎。瓣膜性心脏炎的最常见原因是风湿性心脏疾病（RHD），在全球范围内影响> 3000万人，每年造成30万人死亡。瓣膜狼疮患者和相关的抗磷脂抗体综合征也发生心脏炎。我们的小组有开创了一个具有病理特征的共存瓣膜性心脏炎和炎症性关节炎的小鼠模型概括人类患者的人。我们的小组是第一个显示髓样细胞在促进瓣膜心炎。特别是，我们表明自身抗体会吸引特定的FC受体巨噬细胞，导致促炎性细胞因子的产生和巨噬细胞极化，导致慢性瓣膜炎症和纤维化。我们已经将细胞因子白介素13（IL-13）确定为这个过程。当前的提案以这些发现为基础，并将其扩展。在这里，我们将确定单元格类型产生IL-13；初步数据表明2型先天淋巴样细胞（ILC2S）。我们还将确定导致IL-13产生增加的途径，重点是内皮细胞产生的细胞因子。类型2 已知免疫反应会促进组织纤维化，这发生在患者的心脏瓣膜中 RHD和我们的小鼠模型，其特征是瓣膜中存在肌纤维细胞。来自这些肌纤维细胞起源于此尚不清楚。我们提出了复杂的细胞谱系跟踪实验鉴定瓣膜性心脏炎中瓣膜间质细胞（VIC）之间的肌纤维细胞祖细胞。了解肌纤维细胞的起源对于针对它们的理论至关重要。最后，我们专注于难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）的问题，而不是右侧 - 在人类患者和小鼠模型中都是如此。存在许多可能性。我们的初步数据表明，与2型免疫抑制剂或感应中有关的关键基因和蛋白质的表达生物物理变量（例如氧张力和剪切应力）在左侧和右侧阀之间有所不同正常小鼠。因此，我们建议对心脏瓣膜基因表达进行全面分析确定该左侧预测基础的分子途径。在这些数据的指导下，我们将审问这些途径最有希望的。总而言之，我们将定义免疫细胞的离散种群如何相互作用内皮细胞和VIC引起慢性瓣膜注射和纤维化。此外，我们将揭示为什么心脏左侧的环境促进了感染和纤维化。尽管我们专注于这里瓣膜性心脏炎，我们希望我们的发现可以推广到其他类型的心血管感染，包括动脉粥样硬化。