Characterization of murine CD244 haplotypes with divergent function

具有不同功能的小鼠 CD244 单倍型的表征

• 批准号: 7438901
• 负责人: DOROTHY YUAN
• 金额: $ 31.4万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7438901
• 关键词: Accounting; Adaptor Signaling Protein; Address; Affect; Affinity; Alleles; Area; Binding; Biology; CD8B1 gene; Cell-Mediated Cytolysis; Cells; Cellular biology; Congenic Strain; Cytoplasmic Tail; Dendritic Cells; Disease; Docking; Eating; Exhibits; Family; Future; Gene Cluster; Genetic Polymorphism; Goals; Haplotypes; Hematopoietic; Human; Immune response; Laboratories; Lead; Ligands; Lupus; Lymphocyte; Modeling; Molecular; Mouse Strains; Mus; Mutation; Natural Killer Cells; Pathologic; Pathology; Phosphotyrosine; Regulation; Relative (related person); Reporting; Role; SLAM family receptor; Sequence Analysis; Signal Transduction; Staging; Syndrome; T-Lymphocyte; Testing; Transcript; Transgenic Mice; Transgenic Organisms; Tyrosine; X-Linked lymphoproliferative disorders; base; cytokine; cytotoxicity; immune function; mast cell; monocyte; receptor; response; tumor

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.

SLAM受体家族正在成为免疫反应微调的关键参与者， 促进淋巴细胞：淋巴细胞相互作用。它们能够发挥抑制或刺激的作用 受体依赖于它们与关键信号传导衔接子的结合，所述衔接子结合到酪氨酸基序， 它们的细胞质尾巴SLAM家族受体CD244在所有NK细胞上表达，并且能够 调节NK细胞介导的细胞毒性和细胞因子分泌。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功能的丧失也有助于 致命综合症XLP我们最近发现，在小鼠中，两个主要的单倍型（B和z）的基因， SLAM家族基因簇的存在和单倍型分歧已与狼疮的小鼠模型。 我们研究了这些单倍型背景下的CD244功能，发现CD244单倍型的多态性与CD244单倍型相关。 CD 244基因座导致CD 244的功能趋异，其中z单倍型表现为激活，而B单倍型表现为激活。 单体型抑制信号传导。定义这些多态性如何导致不同的CD244功能， 这对NK细胞生物学以及先天免疫和适应性免疫之间的界面的影响 应对措施是我们的长期目标。我们建议在以下具体目标中解决这一问题： 1.阐明CD244功能差异的分子机制。2.完成网站 转基因小鼠品系的差异仅在于它们的CD244等位基因的表达。3.为了检查影响 不同的CD244功能对NK细胞对肿瘤的反应。