Structure and Function of the Lymphocyte Fce Receptor
淋巴细胞 Fce 受体的结构和功能
基本信息
- 批准号:7579833
- 负责人:
- 金额:$ 25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1989
- 资助国家:美国
- 起止时间:1989-05-01 至 2013-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAllergicAllergic rhinitisAnimalsAntibodiesAreaAsthmaB-LymphocytesBackcrossingsBindingBiological ModelsCell surfaceCleaved cellCollaborationsDataDiseaseDominant-Negative MutationEosinophiliaExhibitsFundingGenesHelminthsHumanIDEC-152 Monoclonal AntibodyIgEIgE ReceptorsIn VitroInjection of therapeutic agentKainic AcidLaboratoriesLectinLow affinity IgE receptorLymphocyteLymphocyte FunctionMediatingMessenger RNAMetalloproteasesModelingMonoclonal AntibodiesMouse StrainsMusNatural ImmunityPatientsPeptide HydrolasesPharmacologic SubstancePhenotypePlayPreparationPrincipal InvestigatorProductionProtocols documentationPublishingRattusReagentRegulationRelative (related person)RoleSerumSeveritiesSeverity of illnessSignal TransductionSignaling MoleculeSmall Interfering RNAStructureSurfaceSystemTransgenic AnimalsTransgenic MiceTransgenic OrganismsWild Type MouseWorkaluminum sulfateanti-IgEatopycell typechemokinecytokinedisorder controlextracellularimprovedin vivoinhibitor/antagonistinterestmouse modeloverexpressionprogramsreceptorresponserole modeltranscription factor
项目摘要
DESCRIPTION (provided by applicant): Current studies have indicated that antibodies directed against the stalk region of CD23 cause enhancement of IgE synthesis in both the human in vitro and mouse in vivo systems. CD23 transgenic mice, which overexpress CD23 on all lymphocytes and FDCs, exhibit drastically reduced IgE production in both helminth and alum/ag models. The data suggest a model where the role of CD23 is initially to serve as a component of innate immunity to signal for IgE production by becoming destabilized and cleaved and later by overexpressing at the cell surface and modulating IgE production. This continuation application proposes to investigate the mechanism of these effects. Aim#1 examines the mouse system where the destabilizing mab 19G5 gives enhanced IgE synthesis in vivo. In the current funding, the metalloprotease, ADAM10 has been identified as the primary CD23 sheddase in mouse and humans. The role of ADAM10 in allergic disease will be modeled by making transgenic mouse that overexpress ADAM10 or dominant negative ADAM10. In addition, we will examine the mechanism for the 19G5-induced IgE production by investigating the association of CD23 with another negative signaling molecule, LAX, which has recently been shown to both modulate CD23 expression and regulate IgE levels. Aim#2 will investigate the affect of CD23 overexpression and CD23 destabilization on the mouse asthma model with respect to both modulation and exacerbation of disease. We will utilize both IgE and the new ADAM10 transgenics in order to evaluate the mechanism of the suppression of eosinophilia as well as the capacity of CD23 to modulate the asthma phenotype. Aim#3 will investigate the human in vitro IgE synthesis models with respect to the mechanisms involved in IgE synthesis enhancement, seen with anti-stalk antibodies and synthesis suppression, seen with certain anti-lectin mabs. The importance of ADAM10 in human CD23 cleavage and IgE production will also be explored as will the involvement of LAX. Finally, we will determine if IgE production by B cells obtained from normal and allergic subjects is affected differently by destabilization or stabilization of CD23. In summary, these studies examine the mechanism of action of a natural regulator of IgE production, CD23, with the objective of developing protocols to enhance CD23 expression and thereby regulate IgE, and by analogy, allergic disease in which IgE plays a dominant role.Project Narrative: This project examines mechanisms involved in control of IgE synthesis by a natural regulator. The latter is CD23, a low affinity receptor for IgE. Accumulated evidence indicates that cleavage of CD23 by the metalloprotease ADAM10 increases IgE production in both mouse and humans. This application proposes to study mechanisms involved in this regulation in order to develop new protocols to control allergic disease.
描述(由申请人提供):目前的研究表明,针对CD 23茎区的抗体在人体外和小鼠体内系统中都能引起IgE合成的增强。在所有淋巴细胞和FDC上过表达CD 23的CD 23转基因小鼠在蠕虫和明矾/银模型中均表现出显著降低的IgE产生。这些数据表明了一种模型,其中CD 23的作用最初是作为先天免疫的组分,通过变得不稳定和切割,随后通过在细胞表面过表达和调节IgE产生来发出IgE产生的信号。本继续申请提出研究这些效应的机制。目标#1检查小鼠系统,其中不稳定的mAb 19 G5增强了体内IgE合成。在目前的资助中,金属蛋白酶ADAM 10已被确定为小鼠和人类中的主要CD 23脱落酶。将通过制造过表达ADAM 10或显性阴性ADAM 10的转基因小鼠来模拟ADAM 10在变应性疾病中的作用。此外,我们将通过研究CD 23与另一种负信号分子LAX的相关性来研究19 G5诱导的IgE产生的机制,LAX最近被证明可以调节CD 23表达和调节IgE水平。目的#2将研究CD 23过表达和CD 23不稳定对小鼠哮喘模型在疾病调节和加重方面的影响。我们将利用IgE和新的ADAM 10转基因来评估嗜酸性粒细胞增多症的抑制机制以及CD 23调节哮喘表型的能力。目标#3将研究人体外IgE合成模型中涉及IgE合成增强(用抗茎抗体观察到)和合成抑制(用某些抗凝集素单克隆抗体观察到)的机制。ADAM 10在人CD 23裂解和IgE产生中的重要性也将被探索,LAX的参与也将被探索。最后,我们将确定从正常和过敏受试者获得的B细胞的IgE产生是否受到CD 23的不稳定或稳定的不同影响。总之,这些研究探讨了IgE产生的天然调节剂CD 23的作用机制,目的是制定方案,以增强CD 23的表达,从而调节IgE,并通过类比,过敏性疾病,其中IgE起着主导作用。后者是CD 23,一种IgE的低亲和力受体。累积的证据表明,由金属蛋白酶ADAM 10切割的CD 23增加了小鼠和人类的IgE产生。本申请提出研究参与这种调节的机制,以开发控制过敏性疾病的新方案。
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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DANIEL H CONRAD其他文献
DANIEL H CONRAD的其他文献
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{{ truncateString('DANIEL H CONRAD', 18)}}的其他基金
BIACORE 3000 : IMMUNOLOGY, PROTEIN INTERACTIONS STUDIES,; LYME DISEASE
BIACORE 3000:免疫学、蛋白质相互作用研究;
- 批准号:
7166167 - 财政年份:2005
- 资助金额:
$ 25万 - 项目类别:
BIACORE 3000 : PROTEIN-NUCLEIC ACID INTERACTIONS, T CRUZI STUDIES
BIACORE 3000:蛋白质-核酸相互作用,T CRUZI 研究
- 批准号:
7166168 - 财政年份:2005
- 资助金额:
$ 25万 - 项目类别:
BIACORE 3000 : PROTEIN DRUG INTERACTION STUDIES
BIACORE 3000:蛋白质药物相互作用研究
- 批准号:
7166169 - 财政年份:2005
- 资助金额:
$ 25万 - 项目类别:
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