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Characterization of a New Mouse Model of Autoimmune Cardiac Valve Disease

自身免疫性心脏瓣膜疾病新小鼠模型的表征

基本信息

批准号：
8101818
负责人：
Bryce Binstadt
金额：
$ 12.88万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8101818
关键词：
Animal Model Antigen-Antibody Complex Antigens Antiphospholipid Syndrome Arthritis Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Carditis Cells Complement 1q Complement Activation Coronary Arteriosclerosis Data Deposition Development Disease Generations Genetic Glucosephosphate Isomerase Goals Heart Heart Valve Diseases Heart Valves Immune Immune system Immunoglobulins Inflammation Inflammatory Injury Joints K/BxN model Knowledge Lead Light Mediating Modeling Mus Pathogenesis Pathologic Pathology Patients Play Production Research Rheumatic Fever Rheumatoid Arthritis Rheumatologic Disorder Risk Role Severities Surface System Systemic Lupus Erythematosus T-Lymphocyte Therapeutic Therapeutic Agents Thrombosis base complement deficiency complement system design innovation mortality mouse model novel small molecule systemic autoimmune disease treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Endothelial activation occurs in many of the systemic autoimmune rheumatologic disorders, including rheumatoid arthritis, systemic lupus erythematosus, the antiphospholipid antibody syndrome, and rheumatic fever. This endothelial activation may lead to coronary artery disease, thrombosis, or cardiac valve inflammation, all of which contribute to the increased mortality risk these patients incur. Understanding the basic mechanisms by which autoimmune diseases lead to endothelial pathology is therefore essential to reduce the burden of such diseases. The K/BxN murine model of arthritis provides a novel system in which to study the interplay between systemic autoimmunity and endothelial pathology. The mechanisms of arthritogenesis in this model are well understood, and include autoantibody formation against a ubiquitously expressed antigen, immune complex formation and deposition on synovial surfaces, recruitment of inflammatory cells and complement activation. Although the inflammatory attack in this model was thought to be restricted to the joints, preliminary data presented herein show that the cardiac valves of K/BxN mice are also inflamed and thickened. This is the first animal model of spontaneous cardiac valve inflammation. The fact that the valve disease occurs in an established murine model of arthritis affords a unique opportunity to dissect the mechanisms by which systemic autoimmunity provokes endothelial injury in the heart. This new model of autoimmune carditis will be characterized via three specific aims, including (1) describing the histopathologic and immunopathologic features of the inflammatory valvular carditis in the K/BxN model, (2) determining the role that B cells and immunoglobulins play in generation of the valve pathology and (3) determining the mechanism(s) by which the complement system regulates the valve pathology, based on the preliminary observation that genetic deficiency of complement component C1q exacerbates carditis severity. It is expected that the knowledge gained by studying this new animal model of autoimmune cardiac valve disease will open further avenues for investigating the mechanisms of endothelial pathology in systemic autoimmune conditions and also lead to innovative therapeutic approaches for patients with such disorders.

描述（由申请人提供）：内皮激活发生在许多系统性自身免疫性风湿病中，包括类风湿性关节炎、系统性红斑狼疮、抗磷脂抗体综合征和风湿热。这种内皮激活可能导致冠状动脉疾病、血栓形成或心脏瓣膜炎症，所有这些都导致这些患者的死亡风险增加。因此，了解自身免疫性疾病导致内皮病变的基本机制对于减少此类疾病的负担至关重要。K/BxN小鼠关节炎模型提供了一个新的系统，在其中研究系统性自身免疫和内皮病理之间的相互作用。该模型中关节炎发生的机制已被充分理解，包括针对普遍表达的抗原的自身抗体形成、免疫复合物形成和滑膜表面上的沉积、炎性细胞的募集和补体激活。虽然认为该模型中的炎症发作仅限于关节，但本文提供的初步数据显示K/BxN小鼠的心脏瓣膜也发炎和增厚。这是第一个自发性心脏瓣膜炎症的动物模型。瓣膜疾病发生在已建立的小鼠关节炎模型中的事实提供了一个独特的机会来剖析全身性自身免疫引起心脏内皮损伤的机制。这种新的自身免疫性心脏炎模型将通过三个特定目的来表征，包括（1）描述K/BxN模型中炎性瓣膜性心脏炎的组织病理学和免疫病理学特征，（2）确定B细胞和免疫球蛋白在瓣膜病理学产生中的作用，以及（3）确定补体系统调节瓣膜病理学的机制，基于补体成分C1 q的遗传缺陷加剧心脏炎严重性的初步观察。预计通过研究这种新的自身免疫性心脏瓣膜病动物模型获得的知识将为研究全身性自身免疫性疾病中内皮病理学机制开辟进一步的途径，并为患有此类疾病的患者带来创新的治疗方法。