Characterization of murine CD244 haplotypes with divergent function
Characterization of murine CD244 haplotypes with divergent function
批准号:
7438901
负责人:
DOROTHY YUAN
金额:
$31.4万
依托单位国家:
美国
项目类别:
财政年份:
2007
资助国家:
美国
项目状态:
已结题
起止时间:
2007-08-01 至 2010-07-31
关键词:
AccountingAdaptor Signaling ProteinAddressAffectAffinityAllelesAreaBindingBiologyCD8B1 geneCell-Mediated CytolysisCellsCellular biologyCongenic StrainCytoplasmic TailDendritic CellsDiseaseDockingEatingExhibitsFamilyFutureGene ClusterGenetic PolymorphismGoalsHaplotypesHematopoieticHumanImmune responseLaboratoriesLeadLigandsLupusLymphocyteModelingMolecularMouse StrainsMusMutationNatural Killer CellsPathologicPathologyPhosphotyrosineRegulationRelative (related person)ReportingRoleSLAM family receptorSequence AnalysisSignal TransductionStagingSyndromeT-LymphocyteTestingTranscriptTransgenic MiceTransgenic OrganismsTyrosineX-Linked lymphoproliferative disordersbasecytokinecytotoxicityimmune functionmast cellmonocytereceptorresponsetumor
中文摘要
SLAM受体家族正在成为免疫反应微调和
促进淋巴细胞:淋巴细胞之间的相互作用。它们既能起抑制作用,也能起刺激作用。
受体依赖于它们与关键信号适配器的关联,这些信号适配器结合到基于酪氨酸的基序
它们的细胞质尾巴。SLAM家族受体CD244在所有NK细胞上都有表达,并能够
调节NK细胞介导的细胞毒作用和细胞因子的分泌。在人类中,它的刺激功能是
完全依赖于与适配器SAP的关联。SAP功能的丧失也是一个原因
致命性综合症,XLP。我们最近发现,在小鼠体内,两种主要的单倍型(b和z)的
SLAM家族基因簇存在,单倍型分化与狼疮小鼠模型有关。
我们已经在这些单倍型的背景下研究了CD244的功能,并发现在
CD244基因座导致CD244的功能分化,其中z单倍型表现为激活,b
单倍型抑制信号。定义这些多态如何导致不同的CD244功能和
对NK细胞生物学的影响以及天然免疫和获得性免疫之间的界面
回应是我们的长期目标。我们建议在以下具体目标中解决这一问题:
1.阐明CD244功能分化的分子机制。2.生成
仅在CD244等位基因表达上存在差异的转基因小鼠品系。3.检查影响
分化的CD244在NK细胞对肿瘤的反应中的作用。
英文摘要
The SLAM family of receptors is emerging as key players in the fine tuning of immune responses and
facilitating lymphocyte:lymphocyte interactions. They are able to function as either inhibitory or stimulatory
receptors depending upon their association with key signaling adaptors that bind to tyrosine based motifs in
their cytoplasmic tails. The SLAM family receptor, CD244 is expressed on all NK cells and is able to
regulate NK cell mediated cytotoxicity and cytokine secretion. In the human, its stimulatory function is
completely dependent on the association with the adaptor, SAP. The loss of SAP function also contributes
to the fatal syndrome, XLP. We have recently found that in the mouse, two major haplotypes (b and z) of the
SLAM family gene cluster exist and haplotype divergence has been associated with a murine model of lupus.
We have studied CD244 function in the context of these haplotypes and found that polymorphisms at the
CD244 locus result in divergent function of CD244 with the z haplotype exhibiting activating and the b
haplotype inhibitory signaling. Defining how these polymorphisms lead to divergent CD244 function and the
consequence of that on NK cell biology and the interface between the innate and adaptive immune
responses are our long-term goals. We propose to address this in the following specific aims:
1. To elucidate the molecular mechanisms responsible for divergent CD244 function. 2. To generate
transgenic mouse strains which differ solely in their expression of CD244 alleles. 3. To examine the affect
of divergent CD244 function on NK cell responses to tumors.
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