Protocadherin 7 and Osteoclast Maturation
原钙粘蛋白 7 和破骨细胞成熟
基本信息
- 批准号:10430027
- 负责人:
- 金额:$ 35.39万
- 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:2020-07-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:ActinsAddressAdhesionsAffectAntibodiesBiological AssayBiological MarkersBiological ProcessBiologyBone MarrowBone Marrow CellsCD 200CadherinsCalciumCell AdhesionCell Adhesion MoleculesCell CommunicationCell MaturationCellsChemicalsChimera organismCoupledCytoplasmic TailDataDiseaseDyesExhibitsExtracellular DomainFibronectinsGenesHematopoieticHomeostasisImmune responseIn VitroInflammationInflammatoryInflammatory ResponseIntegrinsLabelLigatureMeasuresMediatingMediator of activation proteinMembraneMesenchymalModelingMolecularMononuclearMusOncoproteinsOsteoblastsOsteoclastsOsteogenesisPathologicPathologyPathway interactionsPatientsPeriodontitisPhysiologicalPhysiological ProcessesProtein FamilyProtein IsoformsProtein phosphataseProteinsPublishingRegulationRoleScreening ResultSignal PathwaySignal TransductionSliceSmall Interfering RNAStainsStimulusTNFSF11 geneTestingTracerVesicleWorkbisphosphonatebonebone lossbone strengthcell motilityimprovedin vivoinflammatory bone lossinhibitorinterestknock-downlipophilicitymembermicroCTmolecular markerosteoclastogenesisreceptorrho GTP-Binding Proteinsscreeningside effecttherapeutic targettrafficking
项目摘要
Inflammation is known to cause bone destruction by excessive osteoclast (OC) activity in patients with
inflammatory diseases, such as periodontitis. To address the underlying causes of such inflammation-related
bone loss, it is important to understand how the cellular and molecular mechanisms of bone homeostasis
maintained by bone-forming osteoblasts (OBs) and bone-resorbing OCs are perturbed by inflammatory stimuli.
Targeting OC maturation rather than differentiation is of particular interest and provides an added benefit of
avoiding unintentionally inhibiting new bone formation. However, identifying promising therapeutic targets of
OC maturation will require greater understanding of its mechanisms of regulation. Cell adhesion is a
physiologic process critical to both OC maturation and its hallmark feature, multinucleation. In the course of
screening potential genes that regulate OC maturation in vitro, we identified a cell adhesion-related gene,
Pcdh7, a protocadherin member of the cadherin superfamily. We have now generated Pcdh7-/- mice for the
purpose of further studying Pcdh7 in OC maturation and inflammatory responses, and therefore propose the
following specific aims: 1. Investigate the role of Pcdh7 in OC differentiation, function, and inflammatory bone
loss. We will employ Pcdh7-/- bone marrow (BM) cells to examine expression of known biological markers and
cell biological functions, including adhesion, motility, actin ring formation, ruffled border formation, and vesicle
trafficking. Pcdh7floxed mice and BM chimeras will be generated for the purpose of more precisely interrogating
OC- versus OB-specific (or other) Pcdh7 functions in the context of bone homeostasis. These mice will also be
employed to confirm the importance of OC-expressed Pcdh7 in the context of inflammatory bone loss and
immune responses that occur after LPS treatment or ligature-induced periodontitis. Together, these studies
should elucidate the cell-specific roles of Pcdh7 in OC maturation and pathologic bone loss. 2. Investigate
mechanisms of Pcdh7 molecular function within OC biology. To investigate how OC-expressed Pcdh7 protein
regulates cell adhesion and/or signal transduction, we will test a four-step model. For each step, we will test
OC maturation, cell adhesion, and activation of signaling pathways, and will employ both physiologically-
activated and hCD3-inducible retroviral (RV) Pcdh7 constructs. First, we will test whether Pcdh7 mediates cell-
cell interactions that activate Pcdh7 intracellular signaling by separately track WT and Pcdh7-/- OCs in mixed
heterotypic OC cultures. Second, we will test the effects of cytoplasmic domain truncation isoforms of Pcdh7
by assaying physiologic expression in OCs and then by RV-expressing isoforms in OCs. Third, we will test
whether and, if so, how Pcdh7 mediates intracellular signaling via the oncoprotein SET. Fourth, we will employ
siRNA and chemical inhibitors to test the relative contributions of Pcdh7-dependent activation of various
signaling pathways to Pcdh7-mediated OC adhesion and maturation. Together, these studies will improve our
understanding of the function of Pcdh7 protein generally, and more specifically, how it controls OC maturation.
已知炎症通过过度的破骨细胞(OC)活性在患有骨质疏松症的患者中引起骨破坏。
炎症性疾病,如牙周炎。为了解决这种炎症的根本原因-牙周炎相关
骨丢失,重要的是要了解如何骨稳态的细胞和分子机制
由骨形成成骨细胞(OB)和骨吸收OC维持的骨代谢受到炎症刺激的干扰。
靶向OC成熟而不是分化是特别令人感兴趣的,并且提供了额外的益处,
避免无意中抑制新骨形成。然而,确定有前途的治疗靶点,
OC的成熟需要对其调控机制有更深入的了解。
这是一个对OC成熟及其标志性特征多核化至关重要的生理过程。
通过筛选可能调控OC体外成熟的基因,我们鉴定了一个与细胞粘附相关的基因,
Pcdh 7,钙粘蛋白超家族的原钙粘蛋白成员。我们现在已经产生了Pcdh 7-β/-β小鼠,
目的进一步研究Pcdh 7在OC成熟和炎症反应中的作用,并提出Pcdh 7在OC成熟和炎症反应中的作用机制。
具体目的如下:1.研究Pcdh 7在OC分化、功能和炎性骨中的作用
我们将使用Pcdh 7-β/β骨髓(BM)细胞来检查已知生物标记物的表达,
细胞生物学功能,包括粘附、运动、肌动蛋白环形成、皱褶边缘形成和囊泡
将产生Pcdh 7 f loxed小鼠和BM嵌合体,用于更精确地询问
在骨稳态的背景下,OC-β相对于OB-β特异性(或其他)Pcdh 7功能。
用于证实OC-10表达的Pcdh 7在炎性骨丢失中的重要性,
LPS治疗或结扎引起的牙周炎后发生的免疫反应。总之,这些研究
Pcdh 7在OC成熟和病理性骨丢失中的细胞特异性作用
Pcdh 7在OC生物学中的分子功能机制。
调节细胞粘附和/或信号转导,我们将测试一个四步模型。对于每一步,我们将测试
OC成熟,细胞粘附和信号通路的激活,并将利用生理学上的
首先,我们将测试Pcdh 7是否介导细胞凋亡,
细胞相互作用,激活Pcdh 7细胞内信号传导,通过分别跟踪WT和Pcdh 7-β/β-cyclocs在混合
第二,我们将测试Pcdh 7的胞质结构域截短同种型的影响,
通过测定OC中的生理表达,然后通过测定OC中的RV-β表达亚型。第三,我们将测试
Pcdh 7是否以及如果是,如何通过癌蛋白SET介导细胞内信号传导。第四,我们将使用
siRNA和化学抑制剂来测试Pcdh 7-β 2依赖性活化的各种细胞的相对贡献。
Pcdh 7-β 1介导的OC粘附和成熟的信号通路。总之,这些研究将提高我们对OC粘附和成熟的认识。
了解Pcdh 7蛋白的功能,更具体地说,它如何控制OC成熟。
项目成果
期刊论文数量(0)
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{{ truncateString('YONGWON CHOI', 18)}}的其他基金
IgSF11 Signaling Controls Osteoclast Maturation and Pathogenic Bone Loss
IgSF11 信号传导控制破骨细胞成熟和致病性骨质流失
- 批准号:
10544787 - 财政年份:2022
- 资助金额:
$ 35.39万 - 项目类别:
IgSF11 Signaling Controls Osteoclast Maturation and Pathogenic Bone Loss
IgSF11 信号传导控制破骨细胞成熟和致病性骨质流失
- 批准号:
10337682 - 财政年份:2022
- 资助金额:
$ 35.39万 - 项目类别:
Regulation of T cell responses to oral antigens
T 细胞对口腔抗原反应的调节
- 批准号:
9306661 - 财政年份:2017
- 资助金额:
$ 35.39万 - 项目类别:
Dendritic Cell-Mediated Oral Antigen Tolerance and the Lung
树突状细胞介导的口腔抗原耐受和肺
- 批准号:
9238657 - 财政年份:2016
- 资助金额:
$ 35.39万 - 项目类别:
Cell Adhesion Regulation of Osteoclast Maturation
破骨细胞成熟的细胞粘附调节
- 批准号:
9899199 - 财政年份:2016
- 资助金额:
$ 35.39万 - 项目类别:
Dendritic Cell-Mediated Oral Antigen Tolerance and the Lung
树突状细胞介导的口腔抗原耐受和肺
- 批准号:
9086712 - 财政年份:2016
- 资助金额:
$ 35.39万 - 项目类别:
Identifying Rare Subtypes of CD8 T-cells Using Single Cell Reactors
使用单细胞反应器鉴定 CD8 T 细胞的稀有亚型
- 批准号:
9086041 - 财政年份:2016
- 资助金额:
$ 35.39万 - 项目类别:
Identifying Rare Subtypes of CD8 T-cells Using Single Cell Reactors
使用单细胞反应器鉴定 CD8 T 细胞的稀有亚型
- 批准号:
9262845 - 财政年份:2016
- 资助金额:
$ 35.39万 - 项目类别:
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