Role of a novel IL18 binding protein in atherosclerosis
新型 IL18 结合蛋白在动脉粥样硬化中的作用
基本信息
- 批准号:8882740
- 负责人:
- 金额:$ 42.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-08-21 至 2019-05-31
- 项目状态:已结题
- 来源:
- 关键词:AdhesionsAffectAffinityAgeAldosteroneAngiotensin IIAortaApolipoprotein EApoptosisAreaArterial Fatty StreakAtherosclerosisBindingBiological ModelsBlood VesselsBone Marrow CellsCCL2 geneCOS-7 CellCardiovascular systemCationsCell ProliferationCell surfaceCellsChestChloride IonChloridesCongestive Heart FailureCytokine SignalingDepositionDevelopmentDiseaseDistal convoluted renal tubule structureEndothelial CellsEventFutureGeneticHealthHeartHumanHypokalemic alkalosisHypomagnesemiaIL6 geneInflammationInflammatoryInheritedInterferon Type IIInterleukin-1 betaInterleukin-18Ion ChannelIon Channel ProteinKidneyKnowledgeLeadLesionLipidsMediatingMetolazoneMolecularMusPathway interactionsPatientsPhenotypePhosphorylation SitePhosphotransferasesProductionProteinsRecombinant Interleukin-18RoleSecondary toSerumSeveritiesSignal PathwaySignal TransductionSmooth Muscle MyocytesSodium ChlorideSodium-Restricted DietSyndromeT-LymphocyteTestingTumor Necrosis Factor-alphaTyrosine Phosphorylationabdominal aortaage relatedaortic archatherogenesiscardiovascular risk factorcell motilitychemokinecytokinehypertensive heart diseaseinterleukin-18 binding proteininterleukin-18 receptorintraperitonealmacrophagenoveloverexpressionreceptorsymporteruptake
项目摘要
DESCRIPTION (provided by applicant): Na-Cl co-transporter (NCC) is a 125-kDa 12-transmembrane Na+-dependent cation-chloride co-transporter that is primarily expressed in kidney distal convoluted tubules to resorb the filtered load of NaCl in the kidney. In mice, deficiency of NCC causes Gitelman syndrome, an inherited hypokalemic alkalosis with significant hypocalciuria and hypomagnesemia, which are secondary to the deficit in NaCl resorption. Interleukin 18 (IL18) is an inflammatory cytokine that promotes inflammatory cell cytokine/chemokine (e.g., IFN-γ, IL6, MCP-1) production. In atherosclerotic lesions, increased levels of IL18 and its cognate receptor IL18r are detected in macrophages, smooth muscle cells (SMCs), and endothelial cells (ECs). Serums IL18 levels are elevated in patients with CAD, correlate with CAD severity score, are associated with cardiovascular risk factors, and predict future CAD events. In experimental atherosclerosis, overexpression or intraperitoneal administration of IL18 increases atherosclerotic lesion formation and enhances vulnerable plaque phenotypes via an IFN-γ- dependent pathway, while inactivation or genetic deficiency of IL18 slows lesion progression. Our preliminary studies show that IL18 binds to NCC and mediates downstream protein tyrosine phosphorylation in mouse heart ECs. Stimulation of macrophages, T cells, and aortic SMCs and ECs with inflammatory cytokines (e.g., IL18, TNF-α, IL1ß) induces NCC expression. In both humans and mice, normal aortas express negligible NCC and IL18r, but SMCs, ECs, and macrophages in atherosclerotic lesions express high amounts of both NCC and IL18r. In atherosclerosis-prone apolipoprotein E-deficient (Apoe-/-) mice, the absence of either IL18r or NCC does not slow atherosclerosis development significantly. But combined deficiency of IL18r and NCC significantly reduces aortic arch macrophage content and lesion areas, and thoracic-abdominal aorta lipid deposition, along with reduced serum cytokines IFN-γ and IL6. From cultured macrophages, the combined absence of NCC and IL18r impairs IL18-mediated cell signaling, and significantly reduces IL18 cell-surface binding and consequent inflammatory cytokine and chemokine production. These observations lead to our central hypothesis that NCC and IL18r are alternative IL18-binding molecules on inflammatory cells and cardiovascular cells, and that they mediate IL18 activities cooperatively in atherogenesis and possibly in other inflammatory diseases. We propose three aims: 1). to examine whether inhibition, activation, or genetic deficiency of NCC affects atherogenesis; whether NCC activities on inflammatory cells (e.g. macrophages) are essential to atherogenesis; and age-dependent; 2). To examine whether NCC acts like other kinase receptor, NCC activities in salt uptake and IL18 signaling interplay with each other, IL18 has different affinity for NCC and IL18r, and NCC is specific for IL18; and 3). To examine whether NCC mediates IL18 activities in T cells and vascular SMCs and ECs.
描述(由申请人提供):Na-Cl协同转运蛋白(NCC)是一种125-kDa 12-跨膜Na+依赖性阳离子-氯化物协同转运蛋白,主要在肾脏远曲小管中表达,以吸收肾脏中的NaCl过滤负荷。在小鼠中,NCC缺乏导致Gitelman综合征,这是一种遗传性低钾血症,伴有显著的低钙尿和低镁血症,继发于NaCl再吸收缺陷。白细胞介素18(IL 18)是促进炎性细胞因子/趋化因子(例如,IFN-γ、IL 6、MCP-1)产生。在动脉粥样硬化病变中,在巨噬细胞、平滑肌细胞(SMC)和内皮细胞(EC)中检测到IL 18及其同源受体IL 18 r水平增加。血清IL 18水平在CAD患者中升高,与CAD严重程度评分相关,与心血管危险因素相关,并预测未来的CAD事件。在实验性动脉粥样硬化中,IL 18的过表达或腹膜内给药增加动脉粥样硬化病变形成并通过IFN-γ依赖性途径增强易损斑块表型,而IL 18的失活或遗传缺陷减缓病变进展。我们的初步研究表明,IL 18与NCC结合并介导小鼠心脏EC中下游蛋白酪氨酸磷酸化。用炎性细胞因子(例如,IL 18、TNF-α、IL 18)诱导NCC表达。在人类和小鼠中,正常动脉粥样硬化表达可忽略的NCC和IL 18 r,但动脉粥样硬化病变中的SMC、EC和巨噬细胞表达大量的NCC和IL 18 r。在易患动脉粥样硬化的载脂蛋白E缺陷(Apoe-/-)小鼠中,IL 18 r或NCC的缺失并不能显著减缓动脉粥样硬化的发展。但IL 18 r和NCC联合缺乏显著降低主动脉弓巨噬细胞含量和病变面积,以及胸腹主动脉脂质沉积,沿着血清细胞因子IFN-γ和IL 6降低。从培养的巨噬细胞,NCC和IL 18 r的组合缺乏损害IL 18介导的细胞信号传导,并显著降低IL 18细胞表面结合和随后的炎性细胞因子和趋化因子产生。这些观察结果导致我们的中心假设,即NCC和IL 18 r是炎性细胞和心血管细胞上的替代性IL 18结合分子,并且它们在动脉粥样硬化形成和可能在其他炎性疾病中协同介导IL 18活性。我们提出三个目标:1)。检查NCC的抑制、激活或遗传缺陷是否影响动脉粥样硬化形成;炎症细胞(例如巨噬细胞)上的NCC活性是否是动脉粥样硬化形成所必需的;以及年龄依赖性; 2).为了检查NCC是否像其他激酶受体一样起作用,NCC在盐摄取和IL 18信号传导中的活性彼此相互作用,IL 18对NCC和IL 18 r具有不同的亲和力,并且NCC对IL 18具有特异性;和3)。检测NCC是否介导T细胞和血管SMC和EC中的IL 18活性。
项目成果
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Role of group 2 innate lymphoid cells in myocardial infarction
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- 批准号:
10365354 - 财政年份:2021
- 资助金额:
$ 42.04万 - 项目类别:
Role of group 2 innate lymphoid cells in myocardial infarction
第 2 组先天淋巴细胞在心肌梗死中的作用
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Role of ILC2 and eosinophils in abdominal aortic aneurysm
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10322053 - 财政年份:2021
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Role of ILC2 and eosinophils in abdominal aortic aneurysm
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10538557 - 财政年份:2021
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Role of a novel IL18 binding protein in atherosclerosis
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- 批准号:
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$ 42.04万 - 项目类别:
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