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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.

摘要慢性炎症/风湿性疾病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学。的该建议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病风湿性心脏病（RHD），其影响全世界超过3000万人，并且每年导致超过300，000人死亡。瓣膜心脏炎也发生在狼疮和相关的抗磷脂抗体综合征患者中。我们集团开创了一种同时存在瓣膜性心脏炎和炎性关节炎的小鼠模型，在人类患者中重现。我们的小组是第一个显示骨髓细胞在导致心脏瓣膜炎具体来说，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。我们已经确定了细胞因子白细胞介素-13（IL-13）是这个过程目前的提案是在这些调查结果的基础上提出的，并加以扩展。在这里，我们将识别细胞类型产生IL-13;初步数据表明2型先天淋巴样细胞（ILC 2）。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。2型已知免疫应答促进组织纤维化，其发生在患有心脏病的患者的心脏瓣膜中。 RHD和我们的小鼠模型，其特征在于瓣膜中存在肌成纤维细胞。细胞免受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目的：鉴定心瓣膜炎瓣膜间质细胞（VIC）中的心肌成纤维细胞祖细胞。了解肌成纤维细胞的来源对于治疗上靶向它们是关键的。最后，我们关注的是令人费解的为什么心脏瓣膜炎优先影响左侧心脏瓣膜（二尖瓣和主动脉瓣）而不是右侧的-这在人类患者和小鼠模型中都是正确的。存在许多可能性。我们初步数据显示，参与2型免疫或感觉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）在左侧和右侧瓣膜之间不同，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，确定这种左侧偏好背后的分子途径。在这些数据的指导下，我们将审问这些途径中最有希望的。总之，我们将定义免疫细胞的离散群体如何相互作用与内皮细胞和VIC一起引起慢性瓣膜炎症和纤维化。此外，我们将揭示为什么心脏左侧的环境促进炎症和纤维化。虽然我们在这里关注的是对于心瓣膜炎，我们希望我们的发现能推广到其他类型的心血管炎症，包括动脉粥样硬化。