Macrophages as effectors of autoimmune valvular carditis
巨噬细胞作为自身免疫性瓣膜性心脏病的效应器
基本信息
- 批准号:8890874
- 负责人:
- 金额:$ 36.6万
- 依托单位:
- 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 2019-06-30
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAnimal ModelAnti-Inflammatory AgentsAnti-inflammatoryAntigen-Antibody ComplexArthritisAttentionAutoantibodiesAutoimmune DiseasesAutoimmune ProcessAutomobile DrivingB-LymphocytesBiological ModelsBiologyCD4 Positive T LymphocytesCardiovascular DiseasesCardiovascular systemCarditisCell Differentiation processCell Surface ReceptorsCellsChronicDataDepositionDiseaseEquilibriumFc ReceptorFibrosisGenesGoalsHealthHeart ValvesHumanImmunoglobulin GInfiltrationInflammationInflammatoryInflammatory ResponseInjuryIntegrin alpha4beta1Interferon Type IIInterleukin-1Interleukin-17Interleukin-18K/BxN modelKnowledgeLeadLupusMacrophage ActivationMediatingMethodsModelingMolecularMorbidity - disease rateMyeloid CellsOutcomePathogenesisPathologyPathway interactionsPatientsPhenotypePlayPopulationProductionReceptor SignalingRecruitment ActivityRelative (related person)RheumatismRheumatoid ArthritisRoleSeveritiesSeverity of illnessSystemSystemic Lupus ErythematosusT-LymphocyteTLR4 geneTNF geneTestingTissuesarginaseautoimmune arthritisautoreactivityburden of illnesscell typechronic autoimmune diseasecytokineimprovedin vivoinsightknockout animalmacrophagemonocytemortalitymouse modelneutrophilnovelsystemic autoimmune diseasetoll-like receptor 4tool
项目摘要
DESCRIPTION (provided by applicant): Our long-term goal is to understand how cardiovascular tissues are targeted for attack in the context of systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. In this proposal we focus on macrophages, a key inflammatory cell type. Although the presence of macrophages in inflamed cardiovascular tissues in patients with these diseases has long been recognized, the tools to dissect their precise role in disease pathogenesis have only recently been developed. We propose to employ these powerful new tools to study how macrophages contribute to cardiovascular inflammation in the setting of systemic rheumatic diseases. We have recently described the occurrence of cardiac valve inflammation in a mouse model of autoimmune arthritis. Valvular carditis in this model is similar to that seen in rheumatic diseases in humans.
The cytokine interleukin-17 (IL-17) and immune complexes interacting with activating Fc receptors are critical for carditis to develop. Importantly, macrophages are the predominant inflammatory cell type in this model. Macrophages are characterized broadly as M1 (classical/pro-inflammatory) or M2 (alternative/anti-inflammatory). Our preliminary data suggest that both of these populations may contribute to valvular carditis. We propose to study essential aspects of macrophage biology in this model system: entry into the cardiovascular tissue, activation, and effector function. First, we will determine how macrophages enter the cardiac valves, focusing on the cell surface receptor VLA-4. Next, we will explore how IL-17, activating Fc receptors and TLR4 drive macrophage activation toward M1 or M2 phenotypes. We will then dissect the relative contributions of the M1 and M2 macrophage populations to disease severity, by interfering with the differentiation of these cell subsets or with their key molecular products.
Using recently-developed conditional gene knockout animals in conjunction with more traditional methods will allow us to interrogate the pathogenic mechanisms employed by macrophages in this system. Immune complexes, IL-17, and macrophage infiltration are hallmarks of many human autoimmune diseases. We propose to use our novel animal model system to begin to understand how these molecules and cells interact in vivo to provoke tissue pathology, with specific attention to the cardiac valves. The knowledge that we gain is expected to lead to new therapies to reduce the cardiovascular morbidity and mortality among patients with rheumatoid arthritis, lupus, and related autoimmune conditions.
描述(由申请人提供):我们的长期目标是了解在类风湿性关节炎和系统性红斑狼疮等系统性自身免疫性疾病的背景下,心血管组织如何成为攻击目标。在本提案中,我们重点关注巨噬细胞,这是一种关键的炎症细胞类型。尽管人们早已认识到患有这些疾病的患者发炎的心血管组织中存在巨噬细胞,但剖析其在疾病发病机制中精确作用的工具直到最近才被开发出来。我们建议利用这些强大的新工具来研究巨噬细胞如何在系统性风湿性疾病中导致心血管炎症。我们最近描述了自身免疫性关节炎小鼠模型中心脏瓣膜炎症的发生。该模型中的瓣膜性心脏炎与人类风湿性疾病中所见的类似。
细胞因子白细胞介素 17 (IL-17) 和免疫复合物与激活的 Fc 受体相互作用对于心脏炎的发生至关重要。重要的是,巨噬细胞是该模型中的主要炎症细胞类型。巨噬细胞的特征大致为 M1(经典/促炎)或 M2(替代/抗炎)。我们的初步数据表明,这两种人群都可能导致瓣膜性心脏炎。我们建议在该模型系统中研究巨噬细胞生物学的基本方面:进入心血管组织、激活和效应器功能。首先,我们将确定巨噬细胞如何进入心脏瓣膜,重点关注细胞表面受体 VLA-4。接下来,我们将探讨 IL-17、激活 Fc 受体和 TLR4 如何驱动巨噬细胞向 M1 或 M2 表型激活。然后,我们将通过干扰这些细胞亚群或其关键分子产物的分化,剖析 M1 和 M2 巨噬细胞群对疾病严重程度的相对贡献。
使用最近开发的条件基因敲除动物与更传统的方法相结合,将使我们能够探究该系统中巨噬细胞所采用的致病机制。免疫复合物、IL-17 和巨噬细胞浸润是许多人类自身免疫性疾病的标志。我们建议使用我们的新型动物模型系统来开始了解这些分子和细胞如何在体内相互作用以引发组织病理学,特别关注心脏瓣膜。我们获得的知识有望带来新的疗法,以降低类风湿关节炎、狼疮和相关自身免疫性疾病患者的心血管发病率和死亡率。
项目成果
期刊论文数量(0)
专著数量(0)
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Bryce Binstadt其他文献
Bryce Binstadt的其他文献
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{{ truncateString('Bryce Binstadt', 18)}}的其他基金
A novel autoinflammatory skin disease in a patient with mutations in alpha-T-catenin
α-T-连环蛋白突变患者的一种新型自身炎症性皮肤病
- 批准号:
10055124 - 财政年份:2020
- 资助金额:
$ 36.6万 - 项目类别:
A novel autoinflammatory skin disease in a patient with mutations in alpha-T-catenin
α-T-连环蛋白突变患者的一种新型自身炎症性皮肤病
- 批准号:
10197026 - 财政年份:2020
- 资助金额:
$ 36.6万 - 项目类别:
Pathogenesis of autoimmune valvular carditis
自身免疫性瓣膜性心脏病的发病机制
- 批准号:
10624894 - 财政年份:2014
- 资助金额:
$ 36.6万 - 项目类别:
Macrophages as effectors of autoimmune valvular carditis
巨噬细胞作为自身免疫性瓣膜性心脏病的效应器
- 批准号:
9086419 - 财政年份:2014
- 资助金额:
$ 36.6万 - 项目类别:
Macrophages as effectors of autoimmune valvular carditis
巨噬细胞作为自身免疫性瓣膜性心脏病的效应器
- 批准号:
8754860 - 财政年份:2014
- 资助金额:
$ 36.6万 - 项目类别:
Pathogenesis of autoimmune valvular carditis
自身免疫性瓣膜性心脏病的发病机制
- 批准号:
10418653 - 财政年份:2014
- 资助金额:
$ 36.6万 - 项目类别:
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