The pathophysiological role of the immunoproteasome in atherosclerosis

免疫蛋白酶体在动脉粥样硬化中的病理生理作用

• 批准号: 8989563
• 负责人: Joerg Herrmann
• 金额: $ 16.55万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8989563
• 关键词: Accounting; Acute myocardial infarction; Advanced Development; American; Apolipoprotein E; Area; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cardiovascular Diseases; Carotid Artery Plaques; Cause of Death; Cell physiology; Cells; Cessation of life; Chronic; Colitis; Cytokine Signaling; Data; Dendritic Cells; Development; Diagnostic; Disease; Disease Pathway; Endothelial Cells; Experimental Models; Fatty acid glycerol esters; Foam Cells; Functional disorder; Genetic; Goals; Health; High Fat Diet; Image; In Vitro; Individual; Inflammation; Inflammatory; Injury; Interferon Type II; Knowledge; Medical; Mission; Modeling; Molecular Profiling; Morbidity - disease rate; Mus; Myocardial Infarction; Patient Care; Patients; Pattern; Population; Process; Public Health; Research; Rheumatoid Arthritis; Risk Factors; Role; Rupture; Shoulder; Signal Transduction; Societies; Structure; T-Lymphocyte; Therapeutic; Tissues; Up-Regulation; Work; base; cardiovascular risk factor; cell transformation; cytokine; expectation; human disease; improved; improved outcome; in vivo; inhibitor/antagonist; innovation; insight; macrophage; monocyte; mortality; mouse model; novel; novel therapeutics; prevent; prognostic; research study; response; theories

DESCRIPTION (provided by applicant): Atherosclerosis continues to progress structurally in one third of patients on optimal medical therapy and every 30 seconds still, an American will have an acute myocardial infarction, and every minute, one will die from one. These data point to the existence of significant gaps in our understanding of this disease process. The long- term goal of the current line of research is, thus, to identify new disease pathways and treatments in atherosclerosis. Studies in other chronic inflammatory diseases have pointed out a phenomenal reduction in tissue inflammation and injury by specific inhibition of the immunoproteasome. Our own preliminary studies demonstrate the expression of immunoproteasome subunits in the shoulder areas of complicated plaques. Guided by these data, the objective of the current application is to determine the expression pattern and pathophysiological significance of the immunoproteasome in an established murine model of atherosclerosis. Our central hypothesis is that the immunoproteasome contributes to the development of advanced atherosclerotic plaques in mice primarily via its activity in bone marrow-derived inflammatory cells. The rationale for these studies is that identification of the role of the immunoproteasome in atherosclerosis will provide further insight into disease mechanisms and novel therapy options. This proposal pursues three specific aims: 1) Determine a) the expression profile of the immunoproteasome in atherosclerosis in apolipoprotein E-deficient (apoE -/-) mice on a high fat diet and b) the effect and mechanisms of action of pharmacological immunoproteasome inhibition in this atherosclerosis model; 2) Determine the leading cell origin of immunoproteasome activity in atherosclerosis; and 3) Determine the role of the immunoproteasome in interferon gamma cytokine signaling on a) endothelial cell function and b) macrophage plasticity. Under aim 1a, apoE-/- mice will be subjected to a high fat diet and the expression profile of the immunoproteasome over the course of atherosclerosis development will be defined. Under aim 1b, apoE-/- mice will be treated with a specific immunoproteasome inhibitor started with (progression model) or after (regression model) the start of the high fat dit. Under aim 2, chimeric bone marrow transplantation experiments will be performed to assess the influence of genetic deficiencies in immunoproteasome subunits in bone marrow-derived inflammatory cells and specifically in CD+ and CD8+ T-cells on experimental atherosclerosis. Under aim 3, the functional significance of the immunoproteasome for interferon gamma signaling in endothelial cells and macrophages will be studied in vitro and in vivo. This proposal is innovative as it will provide first data in atherosclerosis on an increasingly recognized important regulator of inflammation: the immunoproteasome. This proposal is significant because it has the potential to vertically advance our scientific understanding of the atherosclerotic disease process. Ultimately, this is to reduce the burden of atherosclerosis on the individual and society.

描述（由申请人提供）：动脉粥样硬化在最佳药物治疗中的三分之一患者中继续在结构上进展，而且每30秒仍然每30秒，美国人将患有急性心肌梗塞，每分钟，一个人都会死于一个。这些数据表明，在我们对这种疾病过程的理解中存在很大的差距。因此，当前研究线的长期目标是确定动脉粥样硬化中的新疾病途径和治疗方法。在其他慢性炎症性疾病中的研究指出，通过特异性抑制免疫蛋白酶体，组织炎症和损伤的降低显着减少。我们自己的初步研究表明，复杂斑块的肩部区域中免疫蛋白酶体亚基的表达。在这些数据的指导下，当前应用的目的是确定在既定的动脉粥样硬化鼠模型中免疫蛋白酶体的表达模式和病理生理意义。我们的中心假设是，免疫蛋白酶体有助于小鼠中晚期动脉粥样硬化斑块的发展，主要是通过其在骨髓衍生的炎性细胞中的活性。这些研究的理由是，鉴定免疫蛋白酶体在动脉粥样硬化中的作用将进一步了解疾病机制和新型治疗方案。该提案追求三个具体目的：1）确定a）a）在高脂肪饮食和b上，免疫蛋白酶体在载脂蛋白E缺陷型（APOE-/ - ）小鼠中的动脉粥样硬化症状的表达曲线； 2）确定动脉粥样硬化中免疫蛋白酶体活性的主要细胞起源； 3）确定免疫蛋白酶体在干扰素γ细胞因子信号传导中的作用a）内皮细胞功能和b）巨噬细胞可塑性。在AIM 1A下，APOE - / - 小鼠将接受高脂肪饮食，并将在动脉粥样硬化发育过程中进行免疫蛋白酶体的表达特征。在AIM 1B下，APOE - / - 小鼠将使用特定的免疫蛋白酶体抑制剂（进度模型）或后（回归模型）进行高脂肪DIT的开始。在AIM 2下，将进行嵌合骨髓移植实验，以评估骨髓衍生的炎症细胞中免疫蛋白酶体亚基中遗传缺陷的影响，特别是在CD+和CD8+ T细胞中对实验动脉粥样硬化的影响。在AIM 3下，将在体外和体内研究免疫蛋白酶体对内皮细胞和巨噬细胞中干扰素伽马信号传导的功能意义。该提案具有创新性，因为它将在越来越公认的炎症的重要调节剂中提供动脉粥样硬化的第一数据：免疫蛋白酶体。该提案很重要，因为它有可能垂直提高我们对动脉粥样硬化疾病过程的科学理解。最终，这是为了减轻动脉粥样硬化对个人和社会的负担。