Role of Siglec-10/G as a tumor suppressor in B-cells
Role of Siglec-10/G as a tumor suppressor in B-cells
批准号:
9224943
负责人:
Matthew Scott Macauley
金额:
$13.18万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-01-01 至 2017-07-31
关键词:
AffectAgeAntibodiesAntibody AffinityAutoimmunityB-Cell ActivationB-Cell DevelopmentB-Cell LymphomasB-Cell NonHodgkins LymphomaB-LymphocytesBindingBlocking AntibodiesBone MarrowCD4 Positive T LymphocytesCell CommunicationCellsCharacteristicsChimera organismCoculture TechniquesDevelopmentEnhancing LesionEpigenetic ProcessEtiologyEventFamilyGTP-Binding Protein alpha Subunits, GsGlycolipidsGlycoproteinsGoalsHelper-Inducer T-LymphocyteHumanHyperplasiaImmuneImmunityImmunoglobulin Somatic HypermutationImmunoglobulinsIn VitroKineticsKnowledgeLectinLigandsLinkLymphomaLymphomagenesisMalignant - descriptorModelingMusOrthologous GenePatternPhenotypePlayPolysaccharidesPredispositionProcessReactionReceptor CellReceptors, Antigen, B-CellRoleSialic AcidsSomatic MutationSpecificityStructure of germinal center of lymph nodeT-LymphocyteTestingTransgenic MiceTransgenic OrganismsTumor Suppressor Proteinscytokineexperimental studyglycosylationinsightmembermouse modeloverexpressionpathogenpreventreceptorresponsesialic acid binding Ig-like lectinstemtreatment strategy
中文摘要
项目摘要/摘要
大约80%的B细胞性非霍奇金淋巴瘤来源于生发中心(GC)B细胞。
GC B细胞内的体细胞高突变是抗体亲和力成熟所必需的,但体细胞突变
也可以驱动表观遗传损伤,提高存活率,维持GC B细胞的过度增殖状态,
并促进淋巴肿大。考虑到GC B细胞对恶性转化的敏感性,它不是
令人惊讶的是,GC内部的自然选择过程被认为有助于防止
恶性克隆人。因此,需要更深入地了解制约GC的因素。签约-
10/G(人/鼠同源基因)是识别唾液酸的抑制性受体Siglec家族的成员
含酸的葡聚糖配体。Siglec-10/G通过B细胞受体抑制B细胞的激活。在小鼠身上,
Siglec-G在抑制B细胞激活的初始事件中的作用已被描述,但尚不清楚
Siglec-G在后期阶段发挥作用,例如在GC中。有趣的是,扩展的GC间隔是
在Siglec-G-/-小鼠中观察到,Siglec-G-/-小鼠患上B细胞淋巴瘤,Siglec-10表达缺失
GC衍生的B细胞淋巴瘤。综上所述,我们假设Siglec-G在
健康状况和Sigelc-10/G表达缺失促进GC来源的B细胞的发展
由于GC反应控制不佳而导致的淋巴瘤。初步结果支持Siglec-G在
抑制混合骨髓嵌合体中GC-B细胞作为B细胞的反应揭示Siglec-G-/-GC B细胞
逐渐胜过WT GC B细胞。更多的初步证据表明了一种独特的表型
(在Siglec-G-/-小鼠体内GC-Tfh细胞中ICOS表达增加),支持其他
Siglec-G在调节B-T细胞相互作用中的作用的证据。该项目旨在调查一个
Siglec-G基因缺失与GC源性B细胞淋巴瘤发生、发展的因果关系
评估Siglec-G在调节B-T细胞相互作用中的潜在作用。两个独立的方法将是
用来检验Siglec-G-/-的缺失,一种调节失调的GC与GC衍生的B-G-的发展之间的因果关系
细胞性淋巴瘤。在第一种方法中,Tfh细胞将在Siglec-G-/-小鼠身上被消融。在第二种方法中,
在发展成GC-G的独立小鼠模型中,Siglec-G的表达将以转基因方式保持。
衍生的B细胞淋巴瘤和松散的Siglec-G表达。考察Siglec-G的负面作用
作为B-T细胞相互作用的调节因子,Siglec-G的配基特异性将以糖链为参照进行剖析。
天真的GC-Tfh CD4+细胞,以及CD4+T细胞上的葡聚糖配体将被操纵,以检查这将产生什么影响
对B-T细胞的相互作用有影响。该项目的总体目标是测试Siglec-G作为肿瘤的作用
并研究Siglec-G抑制GC的一种可能机制。这
知识将导致对GC来源的B细胞淋巴瘤病因的新见解,并有可能提供
为新的治疗策略提供线索,这对于不治之症的FL尤其需要。
英文摘要
PROJECT SUMMARY/ABSTRACT
Approximately 80% of B-cell non-Hodgkin's lymphomas are derived from germinal center (GC) B-cells.
Somatic hypermutation within GC B-cells is necessary for antibody affinity maturation, but somatic mutations
can also drive epigenetic lesions that enhance survival, maintain the hyperproliferative state of GC B-cells,
and promote lymphomagenesis. Given the susceptibility of GC B-cells to malignant transformation, it is not
surprising that the natural process of selection within the GC is thought to help protect against the selection of
malignant clones. Accordingly, a deeper understanding of factors that restrain the GC are needed. Siglec-
10/G (human/mouse ortholog) are members of the Siglec family of inhibitory receptors that recognize sialic
acid-containing glycan ligands. Siglec-10/G dampen B-cell activation through the B-cell receptor. In mice, the
role of Siglec-G in inhibiting the initial events of B-cell activation have been described, but it is unknown if
Siglec-G plays a role at later stages, such as in the GC. Interestingly, an expanded GC compartment is
observed in Siglec-G-/- mice, Siglec-G-/- mice develop B-cell lymphomas, and Siglec-10 expression is lost on
GC-derived B-cell lymphomas. Taken together, we hypothesize that Siglec-G restrains the GC reaction under
healthy conditions and that loss of Sigelc-10/G expression promotes the development of GC-derived B-cell
lymphomas due to a poorly controlled GC reaction. Preliminary results support a role for Siglec-G in
restraining GC B-cells, as B-cell responses in mixed bone marrow chimeras reveal that Siglec-G-/- GC B-cells
gradually outcompete WT GC B-cells. Additional preliminary evidence demonstrates a unique phenotype
(increased ICOS expression) in GC T-follicular helper (GC-Tfh) cells within Siglec-G-/- mice, supporting other
lines of evidence for a role for Siglec-G in modulating B-T cell interactions. This project aims to investigate a
causal relationship between loss of Siglec-G and the development of GC-derived B-cell lymphomas and
assess a potential role for Siglec-G in regulating B-T cell interactions. Two independent approaches will be
used to test causality between loss of Siglec-G-/-, a dysregulated GC, and the development of GC-derived B-
cell lymphomas. In the first approach, Tfh cells will be ablated in Siglec-G-/- mice. In the second approach,
Siglec-G expression will be maintained transgenically in an independent mouse model that develops GC-
derived B-cell lymphomas and loose Siglec-G expression. To examine a role for Siglec-G as a negative
regulator of B-T cell interactions, the ligand specificity of Siglec-G will be dissected in reference to glycans on
naïve GC-Tfh CD4+ cells, and glycan ligands on CD4+ T-cells will be manipulated to examine what impact this
has on B-T cell interactions. The overall objective of this project is to test the role of Siglec-G as a tumor
suppressor in GC B-cells and examine one potential mechanism by which Siglec-G restrains the GC. This
knowledge will lead to new insights into the etiology of GC-derived B-cell lymphomas, and potentially offer
clues for new treatment strategies, which are especially needed for the incurable FL.
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