Primate Placental MHC Immunogenetics

灵长类动物胎盘 MHC 免疫遗传学

• 批准号: 8719922
• 负责人: THADDEUS G GOLOS
• 金额: $ 18.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-12 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719922
• 关键词: Animal Model; Animals; Biology; Cells; Characteristics; Development; Disease; Elements; Endometrial; Environment; Equilibrium; Evolution; Exhibits; Experimental Models; Family member; Fetal Development; Fetal Growth Retardation; Foundations; Future; Gene Expression; Gene Family; Genetic Polymorphism; Goals; HLA G antigen; HLA-C Antigens; Haplotypes; Histocompatibility Antigens Class I; Homologous Gene; Human; Immune; Immune system; Immunogenetics; Individual; Infection; Leukocytes; MHC Class I Genes; Macaca; Macaca mulatta; Messenger RNA; Modeling; Molecular; Orthologous Gene; Pathology; Personal Satisfaction; Phenotype; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Pregnancy loss; Premature Labor; Primates; Recombinants; Recurrence; Regulation; Rewards; Risk; Role; Spontaneous abortion; System; Testing; Therapeutic; Variant; base; fetal; implantation; in vivo; killer inhibitory receptor; novel; peripheral blood; programs; public health relevance; pyrosequencing; receptor; receptor binding; research study; response; success; therapeutic target; trophoblast

DESCRIPTION (provided by applicant): The unique expression of MHC class I molecules HLA-G and particularly HLA-C in extravillous trophoblasts is thought to be a critical element of human pregnancy. Although their MHC is rapidly evolving, it is clear that other primates have actively retained placental expression of genes orthologous or homologous to HLA-G, and the receptors for MHC class I molecules, the KIR and LILR gene family members, are undergoing parallel evolution and reflect the diversity of their cognate MHC molecules. However, a full understanding of the dialog between placental MHC class I molecules and specific receptors on decidual leukocytes in vivo, and their potential as therapeutic targets in cases of adverse pregnancy outcomes will require better development of appropriate animal models. We have extensively characterized the expression of Mamu-AG, a nonclassical MHC class I molecule with apparently restricted polymorphism expressed in rhesus monkey trophoblasts. We have formulated a new hypothesis that although the rhesus does not have an orthologous MHC-C locus, placental Mamu-AG will fulfill the placental role of human HLA-C. To test this hypothesis and move this important animal model forward, we propose three Specific Aims. Specific Aim 1. To define the polymorphism of placental MHC class I mRNAs expressed in rhesus monkey trophoblasts by high throughput pyrosequencing. Specific Aim 2. To define the expression of KIR and LILR mRNAs in rhesus monkey decidual and peripheral blood leukocytes using a novel pyrosequencing-based phenotyping approach. Specific Aim 3. To express recombinant Fc-tagged rhesus decidual KIR/LILR receptors and use these as probes to identify candidate receptors for placental Mamu-AG. These studies propose to reframe our understanding of rhesus placental MHC expression, and move the field forward by defining the candidate receptors present on rhesus peripheral blood and decidual leukocytes. Defining the Mamu-AG receptor(s) on decidual leukocytes will strengthen interpretation of ongoing and future in vivo experiments with rhesus monkeys in the study of maternal immune recognition and response in implantation, early placental and decidual development, and fetal well-being and pregnancy outcome, as well as placental influences on the endometrial mucosal immunological environment.

描述（由申请人提供）：MHC I类分子HLA-G，特别是HLA-C在上皮外滋养细胞中的独特表达被认为是人类妊娠的关键因素。虽然它们的MHC正在快速进化，但很明显，其他灵长类动物也积极保留了HLA-G同源或同源基因的胎盘表达，MHC I类分子的受体，KIR和LILR基因家族成员，正在经历平行进化，反映了其同源MHC分子的多样性。然而，充分了解胎盘MHC I类分子与体内蜕膜白细胞特异性受体之间的对话，以及它们作为不良妊娠结局病例治疗靶点的潜力，将需要更好地开发合适的动物模型。Mamu-AG是一种非经典MHC I类分子，其多态性在恒河猴滋养细胞中的表达明显受限。我们提出了一个新的假设，尽管恒河猴没有同源的MHC-C位点，胎盘Mamu-AG将履行人类HLA-C在胎盘中的作用。为了验证这一假设并推动这一重要的动物模型向前发展，我们提出了三个具体目标。具体目标目的利用高通量焦磷酸测序技术确定猕猴滋养细胞中胎盘MHC I类mrna的多态性。具体目标2。使用一种新的基于焦磷酸测序的表型方法来定义恒河猴蜕膜细胞和外周血白细胞中KIR和LILR mrna的表达。具体目标3。目的表达重组fc标记的恒河猴个体KIR/LILR受体，并利用这些受体作为探针鉴定胎盘Mamu-AG的候选受体。这些研究建议重新构建我们对恒河猴胎盘MHC表达的理解，并通过定义存在于恒河猴外周血和蜕膜白细胞上的候选受体来推动这一领域的发展。在胚胎着床、胎盘早期和蜕膜发育、胎儿健康和妊娠结局以及胎盘对子宫内膜黏膜免疫环境的影响等方面，恒河猴体内实验中母体免疫识别和应答的定义将加强对这些研究的解释。