Innate Immunity and Mouse Model of Kawasaki Disease

先天免疫与川崎病小鼠模型

• 批准号: 7616062
• 负责人: Danica Jenine Schulte
• 金额: $ 12.97万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7616062
• 关键词: Acute; Affect; Aneurysm; Arteries; Arteritis; Atherosclerosis; Blood Vessels; Bone Marrow; CD8B1 gene; Cardiovascular Diseases; Cell Extracts; Cell Maturation; Cell Wall; Cessation of life; Child; Childhood; Classification; Clinical; Controlled Study; Coronary; Coronary artery; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Endothelial Cells; Etiology; Goals; Heart Diseases; Human; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intraperitoneal Injections; Investigation; Lactobacillus; Lactobacillus casei; Lead; Lesion; Light; Link; Manuscripts; Mediating; Mediator of activation protein; Modeling; Molecular; Mucocutaneous Lymph Node Syndrome; Mus; NF-kappa B; Natural Immunity; Nature; Pathogenesis; Pathology; Patients; Peptidoglycan; Play; Preventive Intervention; Publishing; Receptor Signaling; Reporting; Research Personnel; Role; Signal Transduction; Site; Syndrome; T-Lymphocyte; TLR2 gene; TLR4 gene; Testing; Time; Toll-like receptors; Transgenic Mice; United States; Vascular Diseases; Vasculitis; Wild Type Mouse; arterial lesion; base; clinically relevant; cytokine; improved; in vitro testing; in vivo; insight; lipoteichoic acid; macrophage; mimicry; mouse model; premature atherosclerosis; prevent; programs; response

DESCRIPTION (provided by applicant): Kawasaki disease (KD) is the most common form of acquired heart disease in children, both the etiology and molecular mechanisms leading to the associated coronary arteritis remain unknown. Injection of a cell wall extract derived from Lactobacillus casei; LCCWE, into mice causes coronary arteritis that is histopathologically similar to the arteritis seen in KD, yet injection of a cell wall extract from a closely related strain Lactobacillus paracasei; LpCCWE, does not. The overall goal of this project is to define the molecular mechanisms by which LCCWE causes coronary arteritis, and to explain why LpCCWE does not. Our published data indicate that LCCWE potently induces NF-kB via TLR2 and MyD88 but not TLR4 in vitro (in murine and human macrophages and ECs) and in vivo (TLR2-/- and MyD88-/- mice do not develop coronary lesions). Our recent studies in humans and mice show marked accumulation of mature dendritic cells (DCs) in clinical KD lesions and in mouse arterial lesions after inoculation with LCCWE, suggesting that DCs play an important mechanistic role in coronary arteritis in both clinical KD and in the mouse model of LCCWE-induced arteritis. The hypotheses:(1) lipoteichoic acids and/or peptidoglycans specific to L. casei but not L. paracasei produce coronary arteritis but extracts from L. paracasei do not;(2) DCs are activated by these molecular components, and orchestrate immune response leading to coronary arteritis, and that DCs are essential in triggering this response. Thus, DCs may also play a similarly important function in clinical KD and could respond to DC-targeted therapies. Specific Aims:(1) To define the bioactive component(s) of LCCWE that mediate inflammatory responses and coronary arteritis in this model, and to determine the molecular basis for the differences in response between L. casei and L. paracasei cell wall extracts;(2) To determine whether L. casei and/or L. paracasei cell wall extracts can induce DC activation in vitro using wild type, TLR2-/-, TLR4-/-, and MyD88-/- DCs and to explore the role of DCs in mediating coronary arteritis in vivo using a DC depletion mouse model. Significance: Improved understanding of the molecular mechanisms by which LCCWE leads to coronary arteritis and the role of the innate immune system and DCs in this mouse models may yield important insights into the pathogenesis of arterial inflammatory diseases, and suggest new targets for intervention and prevention of coronary artery pathology in KD.

描述(申请人提供)：川崎病(KD)是儿童获得性心脏病中最常见的形式，导致相关冠脉炎的病因和分子机制尚不清楚。将来自干酪乳杆菌LCCWE的细胞壁提取物注射到小鼠体内会引起冠脉炎，这在组织病理学上类似于KD中看到的动脉炎，但注射来自密切相关菌株Lactobacillusparacasei；LpCCWE的细胞壁提取物不会引起冠脉炎。该项目的总体目标是确定LCCWE引起冠状动脉动脉炎的分子机制，并解释为什么LpCCWE不会。我们发表的数据表明，LCCWE通过TLR2和MyD88有效地诱导了NF-kB，但在体外(在小鼠和人巨噬细胞和内皮细胞中)不能诱导TLR4，在体内(TLR2-/-和MyD88-/-小鼠不会发生冠状动脉病变)。我们最近在人和小鼠身上的研究表明，在临床KD和LCCWE诱导的小鼠动脉炎模型中，成熟树突状细胞(DC)在临床KD和小鼠动脉病变中显著积聚，表明DC在临床KD和LCCWE诱导的小鼠动脉炎模型中都在冠脉炎中起着重要的机制作用。假设：(1)酪乳杆菌特异的脂磷壁酸和/或肽聚糖但不能引起冠脉炎，而副乳杆菌提取物不能引起冠脉炎；(2)树突状细胞被这些分子组分激活，并协调免疫反应导致冠脉炎，树突状细胞在触发这种反应中是必不可少的。因此，DC也可能在临床KD中发挥类似的重要作用，并对DC靶向治疗有反应。具体目的：(1)确定在该模型中介导炎性反应和冠状动脉炎症的生物活性成分(S)，并确定酪乳杆菌和副乳杆菌细胞壁提取物之间反应差异的分子基础；(2)利用野生型、TLR2-/-、TLR4-/-和MyD88-/-DC在体外检测酪乳杆菌和副乳杆菌细胞壁提取物是否能够诱导DC激活，并利用DC耗竭小鼠模型探讨DC在体内介导冠状动脉动脉炎中的作用。意义：进一步了解LCCWE导致冠状动脉炎症的分子机制以及先天免疫系统和DC在该模型中的作用，可能会对动脉炎症性疾病的发病机制提供重要的见解，并为干预和预防KD的冠状动脉病变提供新的靶点。