Role of the CD40/CD40L dyad in atherosclerosis

CD40/CD40L二元体在动脉粥样硬化中的作用

• 批准号: 6874296
• 负责人: Masanori Aikawa
• 金额: $ 37.1万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-03 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6874296
• 关键词: CD40 molecule; atherosclerotic plaque; biological signal transduction; blood coagulation; bone marrow; cell differentiation; cell type; clinical research; fibrinolysis; human tissue; inflammation; laboratory mouse; macrophage; pathologic process; thrombosis; transcription factor; vascular endothelium; vascular smooth muscle

DESCRIPTION (provided by applicant): Originally considered a simple process of progressive blood vessel occlusion by fatty deposits, atherosclerosis is increasingly appreciated as a complex and multifactorial disease. In particular, the identification of atherogenesis as a (chronic) inflammatory disease and the implication of immune mediators contributed to our recent understanding of this prevalent human disease. Previous work by the applicants established a prominent role of the CD40/CD40 ligand (CD40L) dyad in atherogenesis in vitro and in vivo, and furthermore identified the interruption of CD40/CD40L interactions as a potential therapeutic target preventing plaque progression and mediating processes associated with plaque stabilization. The central role of the CD40/CD40L dyad within the immune system, however, may limit the clinical application of the antibody-based approach employed in these studies. This proposal will evaluate the pathophysiologic pathways via which the CD40/CD40L dyad promotes atherogenesis to assist in the design of defined therapeutic strategies for the treatment of this prevalent human disease. Specific Aim I: To characterize the role of CD40L in thrombosis and/or thrombolysis. Preliminary studies of the applicants suggested novel, previously unsuspected, functions of CD40 signaling in thrombosis. The modulation of fibrin clot formation via soluble and/or membrane-associated CD40L will be investigated in vitro and ex vivo, employing murine as well as human blood preparations. Furthermore, the hypothesis that mediators of the coagulation cascade enhance CD40/CD40L expression will be tested. Specific Aim II: To test the hypothesis that EC, SMC, and monocytes/macrophages employ differential signal transduction pathways in CD40/CD40L-mediated atherogenesis. Signal transduction pathways triggered by the ligation of CD40 on EC, SMC, and monocytes/macrophages and inducing mediators relevant to atherosclerosis, e.g., tissue factor, will be characterized. These studies will extend preliminary work by the applicants, implicating TRAFs and distinct transcription factors in CD40 signaling within these atheroma-associated cell types. Specific Aim III: To determine the cell types relevant for CD40/CD4OL-mediated atherogenesis. Preliminary studies by the applicants demonstrated diminished atherosclerosis in Ldlr/CD40L compound mutant mice. Ldlr-, CD40/Ldlr-, and CD40L/Ldlr compound mutant mice will be employed in bone marrow reconstitution studies to characterize the cell type(s) relevant to the CD40/CD40L-mediated formation, progression, and differentiation of atherosclerotic plaques in vivo. The combination of these three specific aims will not only provide novel insights into the role of the CD40/CD40L dyad in atherosclerosis, but may also aid identification of defined therapeutic targets for future treatment.

描述（由申请人提供）：最初被认为是脂肪沉积物的进行性血管阻塞的简单过程，动脉粥样硬化越来越被视为一种复杂而多因素的疾病。特别是，将动脉粥样硬化的鉴定为（慢性）炎症性疾病以及免疫介质的含义有助于我们最近对这种普遍的人类疾病的理解。申请人的先前工作确立了在体外和体内动脉粥样硬化发生中CD40/CD40配体（CD40L）dyad的重要作用，此外，还确定了CD40/CD40L相互作用的中断是一种潜在的治疗靶标，可以防止斑块进展和介导过程与斑块稳定相关。但是，CD40/CD40L二元组在免疫系统中的核心作用可能会限制这些研究中采用的基于抗体的方法的临床应用。该建议将评估CD40/CD40L二元组促进动脉粥样硬化的病理生理途径，以帮助设计定义的治疗策略来治疗这种普遍的人类疾病。特定目的I：表征CD40L在血栓形成和/或溶栓中的作用。对申请人的初步研究表明，CD40信号在血栓形成中的新型（以前没有提及）的功能。通过可溶性和/或膜相关的CD40L的纤维蛋白凝块形成的调节将在体外和离体中进行研究，并采用鼠类和人体的血液制剂。此外，将测试凝血级联反应增强CD40/CD40L表达的假设。具体目标II：检验以下假设：EC，SMC和单核细胞/巨噬细胞在CD40/CD40L介导的动脉粥样硬化中采用差异信号转导途径。 CD40在EC，SMC和单核细胞/巨噬细胞上的连接触发的信号转导途径以及诱导与动脉粥样硬化有关的介体（例如组织因子）的介导子。这些研究将延长申请人的初步工作，这意味着TRAF和CD40信号中的不同转录因子在这些动脉粥样硬化相关的细胞类型中。特定目标III：确定与CD40/CD4OL介导的动脉粥样硬化相关的细胞类型。申请人的初步研究表明，LDLR/CD40L复合突变体小鼠的动脉粥样硬化减少。 LDLR-，CD40/LDLR-和CD40L/LDLR化合物突变体小鼠将用于骨髓重建研究中，以表征与CD40/CD40L介导的形成，进展，进展和vivo中的动脉蛋白plaques相关的细胞类型。这三个特定目的的结合不仅将提供有关CD40/CD40L二元组在动脉粥样硬化中的作用的新见解，而且还可以帮助鉴定确定定义的治疗靶标的未来治疗。