Targeting the Proinflammatory Activity of Integrin Mac-1 for Treatment of Atherosclerosis
靶向整合素 Mac-1 的促炎活性治疗动脉粥样硬化
基本信息
- 批准号:10376780
- 负责人:
- 金额:$ 46.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdhesionsAffectAmino AcidsAnti-Inflammatory AgentsArteriesAtherosclerosisAutoimmune DiseasesBindingBlood VesselsBone MarrowBone Marrow TransplantationC3biCRISPR/Cas technologyCardiovascular DiseasesCell AdhesionCell Differentiation processCellsCessation of lifeComplementCoupledDataDevelopmentDiseaseEffectivenessExhibitsFibrinFoam CellsHigh Fat DietHomologous GeneHumanHyperlipidemiaITGAM geneITGB2 geneIn VitroInflammationInflammatoryInflammatory ResponseIntegrinsKnock-in MouseLesionLeukocytesLigand BindingLinkLoxP-flanked alleleLupusMacrophage-1 AntigenMediatingModelingModern MedicineMolecularMouse StrainsMusMutateMutationPatternPhagocytosisPhenotypePlayPopulationProcessProductionPropertyPublishingReportingRiskRoleScanningSeveritiesSignal PathwaySignal TransductionSupporting CellTamoxifenTestingTherapeuticTherapeutic AgentsTransplantationVariantatheroprotectivebasecostcytokinedesigneffective interventionexperimental studygenome wide association studyin vivoinsightloss of functionloss of function mutationmacrophagemonocytemouse modelmutantnovelnovel strategiesnovel therapeutic interventionpreventreceptorresponsetargeted agenttargeted treatmenttherapeutically effectivevascular inflammation
项目摘要
A major player in the development of inflammatory diseases, such as atherosclerosis, is vascular
macrophages, which are primarily derived from infiltrating monocytes in an integrin-dependent process. Mac-1
(CD11b/CD18, αMβ2 or CR3), a major integrin expressed on macrophages, is generally considered as a
proinflammatory receptor. Surprisingly, we find that Mac-1 deficiency on an LDLR-/- background exacerbates
atherosclerosis, which contradicts published observations obtained using bone marrow transplantation
approaches. To resolve this discrepancy, we performed reciprocal bone marrow transplantation experiments,
and our new data agree with the published results. Unexpectedly, they implicate the existence of a subset of
Mac-1+ resident cells with atheroprotective functions. Also contradicting the paradigm of Mac-1 being a
proinflammatory receptor, we discovered that Mac-1 possesses a novel anti-inflammatory activity (J Exp Med
2007). In support of our original finding, genome-wide association studies have linked loss-of-function Mac-1
variants in human population to a greater risk of lupus, an autoimmune disease that correlates with accelerated
atherosclerosis. Thus, Mac-1 appears to both promote and inhibit the development of inflammatory diseases;
however, the molecular mechanism that confers Mac-1 with these diametrically opposing activities is unknown.
In our preliminary studies, we screened several existing homolog-scanning Mac-1 mutants and identified a
novel Mac-1 variant (D289A290→KH) that abolishes Mac-1’s proinflammatory activity without compromising its
anti-inflammatory functions. Subsequently, we generated a knock-in mouse, Mac-1NA, using the CRISPR/Cas9
technology, in which the homologous residues (N289A290) of murine Mac-1 were mutated. Our preliminary study
revealed that Mac-1-/- and Mac-1NA mice exhibit opposite patterns of inflammatory responses in vitro and in
vivo. Based on these exciting preliminary data, we hypothesize that Mac-1 expressed on a subset of aortic
resident cells plays an atheroprotective role by suppressing vascular inflammation. To test our hypothesis, we
generated a GFP-coupled Mac-1flox mouse, which was subsequently crossed with the tamoxifen-inducible
CX3CR1-CreERT2 mouse. Using this novel CX3CR1-CreERT2;Mac-1flox strain, we successfully tagged resident
macrophages but not monocytes with GFP and simultaneously deleted their Mac-1 expression. We propose to
use this novel mouse strain to identify the atheroprotective subset of Mac-1-expressing resident cells. We will
also establish molecular mechanisms underlying the differential ability of Mac-1-/- and Mac-1NA to regulate
macrophage proliferation, intracellular signaling, and foam cell differentiation during the development of
atherosclerosis. Finally, we will investigate novel strategies to selectively target Mac-1’s proinflammatory
functions and test their effectiveness to reduce atherosclerosis. Completion of this project will provide new
insights into the mechanism by which Mac-1 confers macrophages with pro- or anti-inflammatory properties. It
can also assist us in the design of Mac-1-targeting agents to prevent and treat inflammatory diseases.
在炎症性疾病如动脉粥样硬化的发展中的主要参与者是血管内皮细胞。
巨噬细胞,其主要来源于整合素依赖性过程中的浸润单核细胞。Mac-1
(CD 11b/CD 18,αMβ2或CR 3),一种在巨噬细胞上表达的主要整合素,通常被认为是巨噬细胞的一个重要组成部分。
促炎受体令人惊讶的是,我们发现在LDLR-/-背景下Mac-1缺乏会加剧
动脉粥样硬化,这与使用骨髓移植获得的已发表的观察结果相矛盾
接近。为了解决这一矛盾,我们进行了相互骨髓移植实验,
我们的新数据与发表的结果一致。出乎意料的是,他们暗示了一个子集的存在,
Mac-1+驻留细胞具有抗动脉粥样硬化功能。也与Mac-1作为一个
促炎受体,我们发现Mac-1具有新的抗炎活性(J Exp Med
2007年)。为了支持我们最初的发现,全基因组关联研究将Mac-1功能丧失与
人类群体中的变异与狼疮的风险更大,狼疮是一种自身免疫性疾病,
动脉粥样硬化因此,Mac-1似乎既促进又抑制炎性疾病的发展;
然而,赋予Mac-1这些截然相反的活性的分子机制是未知的。
在我们的初步研究中,我们筛选了几个现有的同源扫描Mac-1突变体,并确定了一个
一种新的Mac-1变体(D289 A290 →KH),它可以消除Mac-1的促炎活性,而不影响其
抗炎功能。随后,我们使用CRISPR/Cas9基因构建了一个基因敲入小鼠Mac-1 NA,
技术,其中鼠Mac-1的同源残基(N289 A290)被突变。我们的初步研究
显示Mac-1-/-和Mac-1 NA小鼠在体外和体内表现出相反的炎症反应模式。
vivo.基于这些令人兴奋的初步数据,我们假设Mac-1在主动脉瘤的一个子集上表达,
驻留细胞通过抑制血管炎症而发挥动脉粥样硬化保护作用。为了验证我们的假设,我们
产生了GFP偶联的Mac-1flox小鼠,随后与他莫昔芬诱导的
CX 3CR 1-CreERT 2小鼠。使用这种新的CX 3CR 1-CreERT 2;Mac-1flox菌株,我们成功地标记了居民
巨噬细胞,而不是单核细胞与GFP,并同时删除其Mac-1的表达。我们建议
使用这种新的小鼠品系来鉴定表达Mac-1的驻留细胞的动脉粥样硬化保护亚群。我们将
还建立了Mac-1-/-和Mac-1 NA调节的差异能力的分子机制,
巨噬细胞增殖,细胞内信号传导,和泡沫细胞分化过程中的发展,
动脉粥样硬化最后,我们将研究选择性靶向Mac-1的促炎症反应的新策略。
功能,并测试其有效性,以减少动脉粥样硬化。该项目的完成将提供新的
深入了解Mac-1赋予巨噬细胞促炎或抗炎特性的机制。它
还可以帮助我们设计Mac-1靶向药物来预防和治疗炎症性疾病。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('LI ZHANG', 18)}}的其他基金
Cerebral endothelial cells derived exosomes as a therapy for cognitive impairment in aged diabetic rats
脑内皮细胞衍生的外泌体作为老年糖尿病大鼠认知障碍的治疗方法
- 批准号:
10601114 - 财政年份:2021
- 资助金额:
$ 46.82万 - 项目类别:
Cerebral endothelial cells derived exosomes as a therapy for cognitive impairment in aged diabetic rats
脑内皮细胞衍生的外泌体作为老年糖尿病大鼠认知障碍的治疗方法
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10380096 - 财政年份:2021
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Cerebral endothelial cells derived exosomes as a therapy for cognitive impairment in aged diabetic rats
脑内皮细胞衍生的外泌体作为老年糖尿病大鼠认知障碍的治疗方法
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Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis
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Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis
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