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
- 来源:
- 关键词:AdhesionsAffectAgingAgonistAmerican Society of Clinical OncologyApoptoticAsialoglycoproteinsAtherosclerosisBCL2 geneBindingBinding SitesBiochemicalBiochemical PathwayBlocking AntibodiesBloodBone MarrowC-terminalCD47 geneCell CommunicationCell Membrane ProteinsCell secretionCell surfaceCellsCellular biologyClinicalClinical TrialsDegenerative DisorderDevelopmentDiseaseDisease remissionEatingEnzymesEventExcisionExposure toExtracellular SpaceFibroblastsGenerationsGlycoproteinsHematopoietic stem cellsHeterogeneityHomeostasisHumanIn VitroIndividualInflammationInflammatoryInvadedInvestigationKDEL MotifKnowledgeLabelLesionLifeLigandsLongevityMacrophageMacrophage ActivationMalignant NeoplasmsMediatingMembraneMolecular ChaperonesMultipotent Stem CellsMusNeoplasmsNeuraminidaseNon-MalignantNormal tissue morphologyPathogenicityPathologicPathway interactionsPeritonealPhagocytesPhagocytosisPhaseProcessProteinsProteolytic ProcessingProteomicsPublishingReportingResearchRestRoleSialic AcidsSialoglycoproteinsSignal TransductionSmooth MuscleSmooth Muscle MyocytesSterilitySurfaceSystemic SclerodermaTLR3 geneTestingTherapeuticTissuesToll-like receptorsTranslatingcalreticulincancer cellcancer typedisorder preventionin vivoleukemic stem celllysyl-aspartyl-glutamyl-leucineneoplastic cellneutrophilnew therapeutic targetnonalcoholic steatohepatitisnoveloverexpressionpreventreceptortherapeutic development
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.
项目摘要
巨噬细胞介导的程序性细胞清除(PrCR)可以清除活细胞。我们已经证明了
这种吞噬过程可以消除癌细胞,这些癌细胞发出‘吃我’的信号,而它们的优势细胞‘不’
吃我的分子受阻。然后,我们进一步将这一点扩展到清除其他致病细胞或“过期”细胞。
我们最近研究的主要新发现是:1.激活的巨噬细胞产生和分泌钙网蛋白
(CRT);2.分泌的CRT与靶细胞表面的去唾液酸聚糖结合,为
巨噬细胞。3.癌细胞和中性粒细胞调节其表面以暴露去唾液酸聚糖结合部位
CRT对巨噬细胞起着‘吃我’的信号作用。我们建议通过结合去唾液酸聚糖和去唾液酸来
巨噬细胞上的前吞噬细胞受体(CD91/LPR1),CRT可将靶细胞连接到巨噬细胞
通过PrCR进行通关。CRT通常是一种驻留的ER蛋白,含有C端KDEL保留信号,但
研究表明,在濒临死亡的细胞中,CRT可以转移到细胞表面。我们发现在巨噬细胞上
通过Toll样受体(TLR)激活,CRT既可以移位到细胞表面,也可以分泌,导致
WT(垂死的)或Bcl2+(活的)腹膜中性粒细胞和癌细胞的PrCR增加
Eat Me‘信号CD47要么不存在,要么被阻断。基于这些发现,我们得出如下结论:(1)为了阐明
影响巨噬细胞的信号,导致CRT移位到细胞表面并分泌可溶性
CRT的形式;(2)阐明调控含有去唾液酸聚糖结合位点的可用性的机制
用于靶细胞上的CRT。阐明PrCR所需的巨噬细胞和靶细胞的单个机制
了解巨噬细胞内的串扰:靶细胞相互作用可以有广泛的治疗作用
这意味着什么。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
人巨噬细胞PrCR的CRT表达和分泌及可执行PrCR的巨噬细胞的异质性
体外和体内无菌炎症。在目标2中,我们将使用蛋白质组学分析来定义和表征
巨噬细胞刺激前后CRT的不同蛋白形式:内质网形态与细胞表面形态
结合的,与可溶性分泌的CRT,与与靶细胞上的去唾液酸聚糖结合的CRT。我们有初步的
有证据表明CRT的分泌型不包含KDEL基序,并且可能的蛋白质降解过程
导致了不同CRT形式的形成。最后,在目标3中,我们将研究启动信令事件和
影响唾液酸添加或去除的酶,其活性决定了暴露于
去唾液酸聚糖,因此CRT与细胞表面的结合注定要被消除。这些研究将使
一种新的机制,巨噬细胞通过它来检测要从体内移除的细胞。我们的
这些发现将与癌症、退行性疾病和炎症性病变具有广泛的相关性,并可能
为改变疾病状况的生活揭示新的治疗目标。
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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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
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
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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
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10247050 - 财政年份:2017
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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
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10458105 - 财政年份:2017
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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
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8627187 - 财政年份:2012
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