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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：
10418653
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 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10418653
关键词：
Affect Anti-Inflammatory Agents Antiphospholipid Syndrome Atherosclerosis Autoantibodies Autoimmune Autoimmune Diseases Automobile Driving Award Biophysics Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Carditis Cause of Death Cell Lineage Cells Cessation of life Chronic Data Disease Endothelial Cells Endothelium Fc Receptor Fibroblasts Fibrosis Gene Expression Gene Expression Profile Gene Proteins 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 Activation Mediating Mediator of activation protein Mesenchymal Mind Mitral Valve Modeling Molecular Morbidity - disease rate Mus Myeloid Cells Myofibroblast Oxygen Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patient-Focused Outcomes Patients Persons Piezo 1 ion channel Population Process Production Research Rheumatic Fever Rheumatic Heart Disease Rheumatism Rheumatoid Arthritis Role Side Study models Sum 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 macrophage 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