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

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被整合,以证明a)大多数斑块 泡沫细胞是血管平滑肌细胞(SMC)来源的并且B)SMC可以经历向过渡的命运转换, 多能细胞可以采用斑块改变表型。尽管这些结果表明SMC具有潜力, 尽管目前大多数动脉粥样硬化的治疗方法对SMC几乎没有直接影响。内吞 SMC吸收脂质并成为动脉壁中泡沫细胞的过程尚不清楚。在 此外,动脉壁中SMC表型转换的潜在机制仍然很大程度上未知。 使用高分辨率成像,3D细胞重建和LDL免疫标记的组合,我们有 最近证明,人和鼠动脉粥样硬化斑块中的泡沫细胞(谱系未知) 通过巨胞饮作用内化LDL。使用SMC谱系追踪的新初步数据识别SMC子集 在体内动脉壁中进行巨胞饮。刺激SMC中LDL的巨胞饮促进 脱分化和表型转换为体外促进噬菌斑的表型。此外,药理学 使用Na+/H+交换器1(NHE 1)阻断剂EIPA阻断巨胞饮作用,可抑制LDL摄取, 在多种动脉粥样硬化的鼠模型中抑制动脉粥样硬化的发生并消除动脉粥样硬化的发展。 初步数据还表明,基质细胞蛋白血小板反应蛋白-1(TSP 1)刺激巨胞饮作用, 通过SMC中的CD 47,导致泡沫细胞形成和表型转换,并且整体Cd 47-/-小鼠受到保护 动脉粥样硬化基于这些观察结果,我们假设SMC巨胞饮驱动 通过泡沫细胞形成和SMC表型转换调节动脉粥样硬化。假设是 通过以下具体目的进行测试:目的1:动脉粥样硬化中SMC通过巨胞饮内化LDL 动脉目的2:SMC特异性抑制巨胞饮作用减弱SMC转分化为斑块, 促进表型和抑制动脉粥样硬化。目的3:TSP 1通过CD 47刺激SMC巨胞饮, 促进SMC表型转换并促进动脉粥样硬化的发展。该提案将采用 SMC特异性敲除小鼠(Nhe 1-/-、Cd 47-/-和Cd 36-/-),原代人和鼠主动脉SMC,血管平滑肌细胞, SMC限制性Cre驱动小鼠模型(Itga 8-CreERT 2 +/-; mTmG+/-)和其他遗传工具,以测试 假说.多种互补技术将用于体外研究SMC巨胞饮作用 (药理学、遗传学、荧光/SEM成像)和体内(TEM/IEM显微镜、SMC特异性Nhe 1 敲除小鼠)。最后,拟议的研究将确定促进SMC泡沫的关键机制 细胞形成和表型转换,并可能确定新的治疗干预目标, 动脉粥样硬化

项目成果

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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:
    8579966
  • 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:
    8725727
  • 财政年份:
    2013
  • 资助金额:
    $ 56.37万
  • 项目类别:

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