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.
炎症性疾病(如动脉粥样硬化)发展的主要参与者是血管
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
LI ZHANG其他文献
LI ZHANG的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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
- 批准号:
10380096 - 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
- 批准号:
10211376 - 财政年份:2021
- 资助金额:
$ 46.82万 - 项目类别:
Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis
整合素 CD11b/CD18 在多发性硬化症中的配体依赖性和细胞类型特异性功能
- 批准号:
9892805 - 财政年份:2019
- 资助金额:
$ 46.82万 - 项目类别:
Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis
整合素 CD11b/CD18 在多发性硬化症中的配体依赖性和细胞类型特异性功能
- 批准号:
10016370 - 财政年份:2019
- 资助金额:
$ 46.82万 - 项目类别:
Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis
整合素 CD11b/CD18 在多发性硬化症中的配体依赖性和细胞类型特异性功能
- 批准号:
10660972 - 财政年份:2019
- 资助金额:
$ 46.82万 - 项目类别:
Ligand-dependent and cell type-specific functions of integrin CD11b/CD18 in multiple sclerosis
整合素 CD11b/CD18 在多发性硬化症中的配体依赖性和细胞类型特异性功能
- 批准号:
10434690 - 财政年份:2019
- 资助金额:
$ 46.82万 - 项目类别:
Combination treatment with Vepoloxamer and tPA for acute stroke
维泊洛沙姆和 tPA 联合治疗急性卒中
- 批准号:
9914137 - 财政年份:2017
- 资助金额:
$ 46.82万 - 项目类别:
Cerebral endothelial derived-exosomes improve cognitive function in aged diabetic rat
脑内皮源性外泌体改善老年糖尿病大鼠的认知功能
- 批准号:
9562948 - 财政年份:2017
- 资助金额:
$ 46.82万 - 项目类别:
Mac-1 coordinates PDGF-CC activation by microglia and promotes BBB opening
Mac-1 协调小胶质细胞激活 PDGF-CC 并促进 BBB 打开
- 批准号:
9084646 - 财政年份:2013
- 资助金额:
$ 46.82万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 46.82万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 46.82万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 46.82万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 46.82万 - 项目类别:
Grant-in-Aid for Early-Career Scientists