SMC macropinocytosis: a novel target in atherosclerotic vascular disease
SMC巨胞饮作用:动脉粥样硬化性血管疾病的新靶点
基本信息
- 批准号:10735697
- 负责人:
- 金额:$ 56.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-05-15 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalActinsAdoptedAntibodiesAortaAreaArterial Fatty StreakArteriesAtherosclerosisAttenuatedBlocking AntibodiesBloodBrainCD36 geneCD47 geneCell LineageCellsCessation of lifeCre driverDataDevelopmentDiseaseFemaleFluorescenceFoam CellsGeneticGenomicsGoalsHumanImageImmunoelectron MicroscopyIn VitroKnockout MiceLeukocytesLigandsLipidsLow-Density LipoproteinsMediatingMembraneMicroscopyMolecularMorbidity - disease rateMusMyocardial InfarctionMyocardiumOther GeneticsOxygenPTPNS1 genePhenotypePhysiologicalPolymersProcessProteinsRegulationResolutionRoleRuptureSignal TransductionSmooth Muscle MyocytesSpecificityStrokeTechniquesTestingTherapeutic InterventionThrombospondin 1Vascular Smooth Muscleeffective therapygenetic approachhigh resolution imaginghuman morbidityhuman mortalityimaging approachin vivoindexinginsightmalemortalitymouse modelnew therapeutic targetnovelpharmacologicpolymerizationpreventprotein aminoacid sequencereceptorreconstructionscavenger receptorsingle-cell RNA sequencingtherapeutic targettooltransdifferentiationuptake
项目摘要
Project Summary
Atherosclerosis is a leading cause of morbidity and mortality globally. Recently, cell lineage tracing, single-cell
RNA sequencing and human genomic studies have been integrated to demonstrate that a) majority of plaque
foam cells are of vascular smooth muscle cell (SMC) origin and b) SMC can undergo a fate switch to transitional,
multipotential cells that can adopt plaque altering phenotypes. Although these results identify SMC as potential
therapeutic targets, most current treatments for atherosclerosis have little direct impact on SMC. The endocytic
processes by which SMC take up lipids and become foam cells in the arterial wall are not clearly defined. In
addition, the mechanisms underlying SMC phenotypic switching in the arterial wall remain largely unknown.
Using a combination of high-resolution imaging, 3D cell reconstruction, and LDL immunolabeling, we have
recently demonstrated that foam cells (lineage unknown) in human and murine atherosclerotic plaques
internalize LDL via macropinocytosis. Novel preliminary data using SMC lineage tracing identifies SMC subsets
performing macropinocytosis in the arterial wall in vivo. Stimulation of macropinocytosis of LDL in SMC promotes
dedifferentiation and phenotype switching into plaque-promoting phenotypes in vitro. Further, pharmacological
blockade of macropinocytosis using the Na+/H+ exchanger 1 (NHE1) blocker, EIPA, inhibits LDL uptake in
atherosclerotic arteries and abrogates atherosclerosis development in multiple murine models of atherosclerosis.
Preliminary data also show that the matricellular protein thrombospondin-1 (TSP1) stimulates macropinocytosis
via CD47 in SMC, leading to foam cell formation and phenotypic switching, and global Cd47-/- mice are protected
from atherosclerosis. Based on these observations, we hypothesize that SMC macropinocytosis drives
atherosclerosis through foam cell formation and regulation of SMC phenotypic switching. The hypothesis will be
tested via the following specific aims: Aim 1: SMC internalize LDL via macropinocytosis in atherosclerotic
arteries. Aim 2: SMC-specific inhibition of macropinocytosis attenuates transdifferentiation of SMC into a plaque-
promoting phenotype and inhibits atherosclerosis. Aim 3: TSP1 via CD47 stimulates SMC macropinocytosis,
promotes SMC phenotypic switching and contributes to atherosclerosis development. The proposal will employ
SMC-specific knockout mice (Nhe1-/-, Cd47-/- and Cd36-/-), primary human and murine aortic SMC, a vascular
SMC-restricted Cre driver mouse model (Itga8-CreERT2+/-; mTmG+/-), and other genetic tools to test the
hypothesis. Multiple complementary techniques will be used to study SMC macropinocytosis in vitro
(pharmacological, genetic, fluorescence/SEM imaging) and in vivo (TEM/IEM microscopy, SMC-specific Nhe1
knockout mice). At their conclusion, the proposed studies will define key mechanism(s) promoting SMC foam
cell formation and phenotypic switching and potentially identify new targets for therapeutic interventions of
atherosclerosis.
项目摘要
动脉粥样硬化是全球发病率和死亡率的主要原因。最近,细胞谱系追踪,单细胞
RNA测序和人类基因组研究已经整合在一起,以证明)大多数斑块
泡沫细胞起源于血管平滑肌细胞(SMC),并且b)SMC可以经历向过渡的命运转换,
可以采用斑块改变表型的多潜能细胞。尽管这些结果表明SMC是潜在的
治疗靶点方面,目前大多数治疗动脉粥样硬化的药物对SMC的直接影响很小。内吞
SMC摄取脂质并成为动脉壁泡沫细胞的过程尚不清楚。在……里面
此外,动脉壁中SMC表型转换的机制在很大程度上仍不清楚。
使用高分辨率成像、3D细胞重建和低密度脂蛋白免疫标记的组合,我们已经
最近证实人和小鼠动脉粥样硬化斑块中的泡沫细胞(谱系未知)
通过巨噬细胞吞噬使低密度脂蛋白内化。使用SMC谱系追踪的新的初步数据识别SMC子集
在体内动脉壁进行巨噬细胞吞噬。刺激SMC巨噬细胞吞噬低密度脂蛋白促进
体外去分化和表型转化为斑块促进表型。此外,药理学
用Na+/H+交换器1(NHE1)阻断剂EIPA阻断巨噬细胞吞噬抑制低密度脂蛋白摄取
在多种动脉粥样硬化的小鼠模型中,可抑制动脉粥样硬化的形成。
初步数据还表明,基质细胞蛋白血栓反应蛋白-1(TSP1)可刺激巨噬细胞吞噬
通过SMC中的CD47,导致泡沫细胞的形成和表型转换,全球CD47-/-小鼠受到保护
死于动脉粥样硬化。基于这些观察,我们假设SMC巨噬细胞增多症驱动
泡沫细胞形成和SMC表型转换调节的动脉粥样硬化。假设将是
通过以下特定目标进行测试:目标1:动脉粥样硬化中的SMC通过巨噬细胞吞噬作用内化低密度脂蛋白
动脉。目的2:SMC特异性抑制巨噬细胞吞噬减少SMC向斑块的转分化。
促进表型,抑制动脉粥样硬化。目的3:TSP1通过CD47刺激SMC巨噬细胞吞噬功能,
促进SMC表型转换,促进动脉粥样硬化的发展。该提案将雇用
SMC特异性基因敲除小鼠(Nhe1-/-,CD47-/-和CD36-/-),原代人和小鼠主动脉SMC,一种血管
SMC限制性Cre驱动小鼠模型(Itga8-CreERT2+/-;mTmG+/-),以及其他用于测试
假设。多项互补技术将用于体外研究SMC巨噬细胞吞噬作用
(药理学、遗传学、荧光/扫描电子显微镜成像)和体内(TEM/IEM显微镜,SMC特异性Nhe1
基因敲除小鼠)。在他们的结论中,拟议的研究将确定促进SMC泡沫的关键机制(S)
细胞形成和表型转换,并有可能确定治疗干预的新靶点
动脉硬化。
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)
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Gabor Csanyi其他文献
Gabor Csanyi的其他文献
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{{ truncateString('Gabor Csanyi', 18)}}的其他基金
Lipid macropinocytosis: a novel target in atherosclerotic cardiovascular disease
脂质巨胞饮作用:动脉粥样硬化性心血管疾病的新靶点
- 批准号:
10172967 - 财政年份:2018
- 资助金额:
$ 56.37万 - 项目类别:
Lipid macropinocytosis: a novel target in atherosclerotic cardiovascular disease
脂质巨胞饮作用:动脉粥样硬化性心血管疾病的新靶点
- 批准号:
10401923 - 财政年份:2018
- 资助金额:
$ 56.37万 - 项目类别:
A Novel Role of Macrophage TSP1-CD47 Signaling in Atherosclerosis
巨噬细胞 TSP1-CD47 信号传导在动脉粥样硬化中的新作用
- 批准号:
9071987 - 财政年份:2015
- 资助金额:
$ 56.37万 - 项目类别:
A Novel Role of Macrophage TSP1-CD47 Signaling in Atherosclerosis
巨噬细胞 TSP1-CD47 信号传导在动脉粥样硬化中的新作用
- 批准号:
9294101 - 财政年份:2015
- 资助金额:
$ 56.37万 - 项目类别:
A Novel Role of Macrophage TSP1-CD47 Signaling in Atherosclerosis
巨噬细胞 TSP1-CD47 信号传导在动脉粥样硬化中的新作用
- 批准号:
9094734 - 财政年份:2015
- 资助金额:
$ 56.37万 - 项目类别:
A Novel Role of Macrophage TSP1-CD47 Signaling in Atherosclerosis
巨噬细胞 TSP1-CD47 信号传导在动脉粥样硬化中的新作用
- 批准号:
8725727 - 财政年份:2013
- 资助金额:
$ 56.37万 - 项目类别:
A Novel Role of Macrophage TSP1-CD47 Signaling in Atherosclerosis
巨噬细胞 TSP1-CD47 信号传导在动脉粥样硬化中的新作用
- 批准号:
8579966 - 财政年份:2013
- 资助金额:
$ 56.37万 - 项目类别:
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