Braking Macrophage Cell-Cell Fusion in the Foreign Body Response
在异物反应中阻止巨噬细胞细胞融合
基本信息
- 批准号:10373536
- 负责人:
- 金额:$ 20.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-11-01 至 2023-10-31
- 项目状态:已结题
- 来源:
- 关键词:Abnormal CellActinsAddressAdhesionsAntibodiesAreaArthritisArtificial ImplantsBacterial InfectionsBiocompatible MaterialsBiological ProcessBlocking AntibodiesBone MarrowBone SurfaceCell LineCell NucleusCell fusionCell membraneCell physiologyCell surfaceCell-Cell AdhesionCellsCharacteristicsChimeric ProteinsClustered Regularly Interspaced Short Palindromic RepeatsCuesCytoplasmCytoskeletonDataDefectDiseaseDynaminElectron MicroscopyEndocytosisEndothelial CellsEpitopesEventFailureForeign BodiesForeign-Body Giant CellsForeign-Body ReactionGiant CellsHematopoieticHumanImmuneImplantIn VitroIndividualInfection ControlInflammatoryIntegral Membrane ProteinInterleukin-13Interleukin-4InvestigationKnock-outKnockout MiceLeadMediatingMediator of activation proteinMedical DeviceMembraneMembrane FusionMetalloproteasesMicroscopyMolecularMonoclonal AntibodiesMusMyelogenousMyeloid CellsNormal Statistical DistributionOsteoclastsOsteogenesisOsteolysisOsteolyticPainParasitic infectionPathologicPathologyPathway interactionsPhenotypePhysiological ProcessesProcessProsthesis LooseningsProteinsRecyclingReplacement ArthroplastySchemeSignal PathwayStructureSystemTherapeuticTherapeutic InterventionTimeTissuesTumor Cell InvasionWorkalanine aminopeptidasebonebone masscell typecytokineimplant materialimplantationin vivomacrophagemedical implantmembrane modelmigrationmouse modelnew therapeutic targetnovelparticleprogenitorprotein expressionreceptor mediated endocytosisrecruitresponsestem cellssyncytintraffickingwound healing
项目摘要
By virtue of their versatility and plasticity, macrophages have the ability to undergo phenotypic
and functional changes in response to microenvironmental cues. One such change is the
formation of multinucleated giant cells via intercellular fusion triggered by certain bacterial or
parasitic infections or implantation of medical devices to induce a foreign body response. We
and others have shown that the transmembrane protein CD13 is a multifunctional molecule
that regulates diverse processes such as tumor cell invasion, immune cell trafficking, receptor
mediated endocytosis and recycling and organization of the actin cytoskeleton. In our
preliminary data, we demonstrate that despite a relatively normal distribution of hematopoietic
components in bone marrow and periphery, CD13KO mice have reduced bone mass with
increased osteoclast (OC) numbers per bone surface area but normal bone formation
parameters. In vitro induction of CD13-deficient myeloid progenitors generated from bone
marrow resulted in hyperfusion to generate multinucleated giant cells (MGCs) or OCs that
were considerably larger in size, contained many more nuclei than those from wild type
progenitors, suggesting that CD13 is a component of common fusion pathways shared by
MGC and OC. We observed that while expression of the key fusion proteins, dynamin and
DC-STAMP, are typically downregulated in mature cells post-fusion, expression of these
proteins is sustained at high levels in multinucleated cells lacking CD13. Thus, CD13 acts as
a brake to restrain a common cell-cell fusion pathway and may be a novel therapeutic target
in pathological conditions mediated by abnormal cell fusion. In this proposal, we will identify
the CD13-dependent mechanisms, molecules and signaling pathways involved in cell-
cell fusion in macrophages undergoing giant cell fusion (Aim 1) and the potential for
fusion-blocking anti-CD13 monoclonal antibodies as therapeutics in vitro and in vivo (Aim
2). We will use our extensive panels of wild type and CD13 knock out primary cells of
mouse and human origin, CD13 blocking or activating antibodies, novel CRISPR-deleted
CD13KO myeloid cell lines along with confocal and spinning disk microscopy and
CD13 knockout mouse models to address these questions.
凭借其多功能性和可塑性,巨噬细胞能够经历表型
以及响应微环境线索的功能变化。其中一项变化是
由某些细菌或细菌触发的细胞间融合形成多核巨细胞
寄生虫感染或植入医疗器械引起异物反应。我们
等人证明跨膜蛋白CD13是一种多功能分子
调节多种过程,如肿瘤细胞侵袭、免疫细胞运输、受体
介导的内吞作用以及肌动蛋白细胞骨架的回收和组织。在我们的
初步数据表明,尽管造血细胞分布相对正常
骨髓和外周成分中,CD13KO小鼠的骨量减少
每个骨表面积的破骨细胞 (OC) 数量增加,但骨形成正常
参数。体外诱导骨生成的 CD13 缺陷型骨髓祖细胞
骨髓过度融合,产生多核巨细胞 (MGC) 或 OC,
与野生型相比,它们的尺寸要大得多,含有更多的细胞核
祖细胞,表明 CD13 是
MGC 和 OC。我们观察到,虽然关键融合蛋白、动力蛋白和
DC-STAMP,通常在融合后的成熟细胞中下调,这些的表达
在缺乏 CD13 的多核细胞中,蛋白质维持在高水平。因此,CD13 充当
抑制共同细胞-细胞融合途径的制动器,可能是一个新的治疗靶点
在异常细胞融合介导的病理条件下。在本提案中,我们将确定
CD13依赖性机制、分子和信号通路涉及细胞-
巨噬细胞中进行巨细胞融合(目标 1)的细胞融合以及潜在的
融合阻断抗 CD13 单克隆抗体作为体外和体内治疗剂(Aim
2)。我们将使用我们广泛的野生型和 CD13 敲除原代细胞组
小鼠和人类来源、CD13 阻断或激活抗体、新型 CRISPR 删除
CD13KO 骨髓细胞系以及共聚焦和转盘显微镜
CD13 敲除小鼠模型可以解决这些问题。
项目成果
期刊论文数量(0)
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Mallika Ghosh其他文献
Mallika Ghosh的其他文献
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{{ truncateString('Mallika Ghosh', 18)}}的其他基金
Braking Macrophage Cell-Cell Fusion in the Foreign Body Response
在异物反应中阻止巨噬细胞细胞融合
- 批准号:
10516745 - 财政年份:2021
- 资助金额:
$ 20.5万 - 项目类别:
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