HLA-G at the Maternal Fetal Interface

母胎界面的 HLA-G

• 批准号: 7499140
• 负责人: JOAN Sherar HUNT
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF KANSAS 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: 2007-04-10 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499140
• 关键词: Alleles; Alternative Splicing; Antigens; Cell physiology; Cells; Chicago; Cities; Class; Classification; Code; Collaborations; Commit; Decidua; Drug or chemical Tissue Distribution; Event; Family; Fertility; Genes; Genetic; Genetic Polymorphism; Genotype; Glycoproteins; Goals; Grant; HLA G antigen; Human; Immune; Infection; Institution; Kansas; Lead; Major Histocompatibility Complex; Maternal-Fetal Exchange; Medical center; Messenger RNA; Monoclonal Antibodies; Mothers; Nucleic Acid Regulatory Sequences; Outcome; Placenta; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Premature Labor; Protein Isoforms; Proteins; Publications; Recombinants; Regulation; Reproductive Immunology; Research; Research Personnel; Role; Technical Expertise; Therapeutic Intervention; Tissue Banks; Tissues; Universities; Woman; Work; cytotrophoblast; experience; implantation; improved; member; novel; programs; reproductive; research study; willingness

Glycoproteins derived from the major histocompatibility complex (MHC) class Ib gene, HLA-G, were first described in human placentas, where they were located in cytotrophoblast (CTB) cells within and adjacent to the maternal decidua. Despite nearly two decades of intensive research, the role(s) of the products of this novel gene remain unclear, although most studies point to a role for HLA-G in regulating immune aspects of semiallogeneic pregnancy. The HLA-G gene has many novel features: the gene contains few polymorphisms in the coding region but multiple polymorphisms in the regulatory regions; at least 7 isoforms are generated by alternative splicing of mRNA derived from a single gene; HLAG has limited tissue distribution that includes high expression in placentas and also demonstrates differential isoform expression in CTB cell subpopulations. In this program application, three investigators from two institutions propose to study the role of placental HLA-G in pregnancy. All three, Dr. Joan Hunt (University of Kansas Medical Center, Kansas City, KS), Dr. Margaret Petroff from the same institution, and Dr. Carole Ober (University of Chicago, Chicago, IL) have extensive experience in reproductive immunology and have focused much of their research on MHC antigens in pregnancy. In Project I, Hunt will investigate mechanisms underlying isoform-specific expression and isoform-specific functions of HLA-G using newly generated recombinant soluble HLA-G glycoproteins and monoclonal antibodies to these proteins. In Project II, Petroff will examine co-expression of HLA-G isoforms and members of the B7 family, and will investigate implications for regulation of immune cell function using stably transfected cells expressing various combinations of HLA-G/B7 proteins. In Project HI, Ober will pursue functional aspects of HLA-G genotypes using newly developed allele-specific probes, and will explore relationships to diminished fertility. The program is supported by two Cores. Core A. Administration, directed by Hunt, will be responsible for assuring integration and publication of the outcomes of the experiments. Core B Tissue Collection and Genotyping, directed by Ober, will collect and supply all investigators with early gestation tissues and tissues from problem pregnancies. This core will also identify polymorphisms in genes relevant to each project. The investigators in this program fully expect that their close and systematic collaboration will comprise a powerful approach to elucidating critical aspects of HLA-G expression, regulation and function, and will ultimately lead to new and improved therapies for impaired fertility.

源自主要组织相容性复合体 (MHC) Ib 类基因 HLA-G 的糖蛋白首次在 人类胎盘，它们位于母体蜕膜内部和邻近的细胞滋养层（CTB）细胞中。 尽管经过近二十年的深入研究，这种新基因产物的作用仍不清楚，尽管 大多数研究指出 HLA-G 在调节半同种异体妊娠的免疫方面发挥着作用。 HLA-G基因 具有许多新颖的特点：该基因在编码区含有很少的多态性，但在编码区含有多种多态性。 监管区域；通过来自单个基因的 mRNA 的选择性剪接产生至少 7 个亚型； HLAG 组织分布有限，包括在胎盘中高表达，并且还表现出差异亚型 CTB细胞亚群中的表达。在该计划申请中，来自两个机构的三名研究人员提出 研究胎盘 HLA-G 在妊娠中的作用。三人都是 Joan Hunt 博士（堪萨斯大学医学中心， 堪萨斯城，堪萨斯州），来自同一机构的玛格丽特·彼得罗夫博士和卡罗尔·奥伯博士（芝加哥大学， 伊利诺伊州芝加哥）在生殖免疫学方面拥有丰富的经验，并将大部分研究重点放在 MHC 上 怀孕期间的抗原。在项目 I 中，亨特将研究亚型特异性表达的潜在机制 使用新生成的重组可溶性 HLA-G 糖蛋白研究 HLA-G 的异构体特异性功能 这些蛋白质的单克隆抗体。在项目 II 中，Petoff 将检查 HLA-G 亚型的共表达和 B7 家族成员，并将研究使用稳定的免疫细胞功能调节的影响 转染细胞表达 HLA-G/B7 蛋白的各种组合。在 Project HI 中，Ober 将追求功能性 使用新开发的等位基因特异性探针来研究 HLA-G 基因型的各个方面，并将探索与减少的关系 生育能力。该程序由两个核心支持。核心 A. 行政部门，由 Hunt 领导，将负责 确保实验结果的整合和发布。核心 B 组织采集和基因分型， 由 Ober 指导，将收集并向所有研究人员提供早期妊娠组织和问题组织 怀孕。该核心还将识别与每个项目相关的基因的多态性。调查人员在这 计划充分期望他们密切和系统的合作将构成一个强有力的方法来阐明 HLA-G 表达、调节和功能的关键方面，最终将导致新的和改进的疗法 对于生育能力受损。