Programmed Cell Removal (PrCR) by Macrophages: recognition and phagocytosis of target cells

巨噬细胞的程序性细胞去除(PrCR):靶细胞的识别和吞噬作用

基本信息

  • 批准号:
    10576906
  • 负责人:
  • 金额:
    $ 40.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Macrophage-mediated programmed cell removal (PrCR) allows clearance of living cells. We have shown that this phagocytic process can eliminate cancer cells that present an ‘eat me’ signal and have their dominant 'don't eat me' molecules blocked. We then further extended this to the clearance of other pathogenic or ‘expired’ cells. The key novel findings of our recent studies are: 1. Activated macrophages produce and secrete calreticulin (CRT); 2. Secreted CRT binds to surface asialoglycans on target cells to create ‘eat me signals' for macrophages. 3. Cancer cells and neutrophiles modulate their surface to expose asialoglycan binding sites for CRT that acts as an ‘eat me’ signal for macrophages. We propose that by binding both to asialoglycans and to pro-phagocytic receptors on macrophages (CD91/LPR1), CRT can bridge target cells to macrophages for clearance via PrCR. CRT is normally a resident ER protein containing a C-terminal KDEL retention signal, but it’s been shown that in dying cells CRT can be translocated to the cell surface. We found that upon macrophage activation via toll-like receptors (TLR), CRT can both translocate to the cell surface and be secreted, leading to increased PrCR of either WT (dying) or Bcl-2+ (viable) peritoneal neutrophils and cancer cells on which the ‘don’t eat me’ signal CD47 is either absent or blocked. Based on these findings we proporse: (1) to elucidate the signals affecting the macrophage that result in CRT translocation to the cell surface and secretion of soluble forms of CRT; (2) to elucidate the mechanisms regulating the availability of asialoglycan-containing binding sites for CRT on target cells. Elucidating the individual mechanisms in macrophages and target cells required for PrCR and understanding the cross-talk within macrophage:target-cell interaction can have broad therapeutic implications. In Aim 1 we will investigate which signals stimulate macrophages to increase cell surface expression and secretion of CRT for PrCR and the heterogeneity of macrophages that can carry out PrCR in vitro and sterile inflammation in vivo. In Aim 2 we will employ proteomic analysis to define and characterize the different proteoforms of CRT originating in macrophages before or after stimulation: the ER form vs. cell-surface- bound, vs. soluble secreted CRT, vs. CRT that is bound to asialoglycans on target cells. We have preliminary evidence that the secreted form of CRT does not contain the KDEL motif and that potential proteolytic processing leads to the formation of the different CRT forms. Lastly in Aim 3 we will study the initiating signaling events and enzymes that affect the addition or removal of sialic acid, the activity of which determines the level of exposed asialoglycans and thus the binding of CRT to the surface of cells destined for elimination. These studies will shed light on a novel mechanism by which macrophages detect cells that are to be removed from the body. Our findings will have a broad relevance to cancer, degenerative disease, and inflammatory lesions and will likely reveal new therapeutic targets for life altering disease conditions.
项目概要 巨噬细胞介导的程序性细胞去除 (PrCR) 可以清除活细胞。我们已经证明 这种吞噬过程可以消除发出“吃我”信号并具有显性“别”信号的癌细胞 吃掉我’分子被封锁。然后,我们进一步将其扩展到清除其他致病或“过期”细胞。 我们最近研究的主要新发现是: 1. 活化的巨噬细胞产生并分泌钙网蛋白 (显像管); 2. 分泌的 CRT 与靶细胞表面的脱唾液酸聚糖结合,产生“吃我信号” 巨噬细胞。 3. 癌细胞和中性粒细胞调节其表面以暴露脱唾液酸聚糖结合位点 CRT 充当巨噬细胞“吃掉我”的信号。我们建议通过结合去唾液酸聚糖和 巨噬细胞上的促吞噬细胞受体 (CD91/LPR1),CRT 可以将靶细胞与巨噬细胞桥接起来, 通过 PrCR 清除。 CRT 通常是一种驻留 ER 蛋白,含有 C 端 KDEL 保留信号,但是 研究表明,在垂死细胞中,CRT 可以转移到细胞表面。我们发现巨噬细胞 通过 Toll 样受体 (TLR) 激活,CRT 既可以转移到细胞表面并被分泌,从而导致 WT(死亡)或 Bcl-2+(存活)腹膜中性粒细胞和癌细胞的 PrCR 增加 “吃我”信号 CD47 要么不存在,要么被阻断。基于这些发现,我们建议:(1)阐明 影响巨噬细胞的信号导致 CRT 易位到细胞表面并分泌可溶性 CRT 形式; (2) 阐明调节含脱唾液酸聚糖的结合位点可用性的机制 用于靶细胞上的 CRT。阐明 PrCR 所需的巨噬细胞和靶细胞的个体机制 并了解巨噬细胞内的串扰:靶细胞相互作用可以具有广泛的治疗作用 影响。在目标 1 中,我们将研究哪些信号刺激巨噬细胞增加细胞表面积 PrCR的CRT表达和分泌以及可进行PrCR的巨噬细胞的异质性 体外和体内无菌炎症。在目标 2 中,我们将采用蛋白质组学分析来定义和表征 刺激之前或之后源自巨噬细胞的 CRT 的不同蛋白质形式:ER 形式与细胞表面形式 结合,与可溶性分泌型 CRT 相比,与与靶细胞上的脱唾液酸聚糖结合的 CRT 相比。我们有初步的 有证据表明 CRT 的分泌形式不包含 KDEL 基序,并且潜在的蛋白水解加工 导致了不同CRT形式的形成。最后,在目标 3 中,我们将研究启动信号事件和 影响唾液酸添加或去除的酶,其活性决定了暴露水平 脱唾液酸聚糖,从而使 CRT 与注定要消除的细胞表面结合。这些研究将揭示 揭示了巨噬细胞检测要从体内移除的细胞的新机制。我们的 研究结果将与癌症、退行性疾病和炎症病变具有广泛的相关性,并且可能 揭示改变生活的疾病的新治疗靶点。

项目成果

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IRVING L. WEISSMAN其他文献

IRVING L. WEISSMAN的其他文献

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{{ truncateString('IRVING L. WEISSMAN', 18)}}的其他基金

NexTGen - STANFORD
NexTGen - 斯坦福
  • 批准号:
    10625700
  • 财政年份:
    2022
  • 资助金额:
    $ 40.47万
  • 项目类别:
Programmed Cell Removal (PrCR) by Macrophages: recognition and phagocytosis of target cells
巨噬细胞的程序性细胞去除(PrCR):靶细胞的识别和吞噬作用
  • 批准号:
    10092925
  • 财政年份:
    2020
  • 资助金额:
    $ 40.47万
  • 项目类别:
Programmed Cell Removal (PrCR) by Macrophages: recognition and phagocytosis of target cells
巨噬细胞的程序性细胞去除(PrCR):靶细胞的识别和吞噬作用
  • 批准号:
    9888242
  • 财政年份:
    2020
  • 资助金额:
    $ 40.47万
  • 项目类别:
Evolutionary Conserved Mechanisms of Neuronal Degeneration and Regeneration
神经元变性和再生的进化保守机制
  • 批准号:
    9979601
  • 财政年份:
    2020
  • 资助金额:
    $ 40.47万
  • 项目类别:
Programmed Cell Removal (PrCR) by Macrophages: recognition and phagocytosis of target cells
巨噬细胞的程序性细胞去除(PrCR):靶细胞的识别和吞噬作用
  • 批准号:
    10328484
  • 财政年份:
    2020
  • 资助金额:
    $ 40.47万
  • 项目类别:
Cellular and molecular analyses of hematopoietic stem cell [HSC] interactions with bone marrow niches to improve HSC engraftment for transplantation and tolerance induction
造血干细胞 [HSC] 与骨髓微环境相互作用的细胞和分子分析,以改善 HSC 植入移植和耐受诱导
  • 批准号:
    9753220
  • 财政年份:
    2018
  • 资助金额:
    $ 40.47万
  • 项目类别:
Stem Cell Biology, Cancer Stem Cell Biology, and Cancer Immunotherapy
干细胞生物学、癌症干细胞生物学和癌症免疫治疗
  • 批准号:
    10247050
  • 财政年份:
    2017
  • 资助金额:
    $ 40.47万
  • 项目类别:
Stem Cell Biology, Cancer Stem Cell Biology, and Cancer Immunotherapy
干细胞生物学、癌症干细胞生物学和癌症免疫治疗
  • 批准号:
    10458105
  • 财政年份:
    2017
  • 资助金额:
    $ 40.47万
  • 项目类别:
Graduate Training in Stem Cell Biology and Regenerative Medicine
干细胞生物学和再生医学研究生培训
  • 批准号:
    10208896
  • 财政年份:
    2017
  • 资助金额:
    $ 40.47万
  • 项目类别:
A search for genes that regulate allogeneic stem cell competition
寻找调节同种异体干细胞竞争的基因
  • 批准号:
    8627187
  • 财政年份:
    2012
  • 资助金额:
    $ 40.47万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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