HLA-G at the Maternal Fetal Interface

母胎界面的 HLA-G

• 批准号: 7792473
• 负责人: JOAN Sherar HUNT
• 金额: $ 94.4万
• 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/7792473
• 关键词: HLA; Maternal; Fetal; Interface

DESCRIPTION (provided by applicant): 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 contributions of these proteins to semiallogeneic pregnancy remain poorly understood. 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; restricted cell and tissue distribution of specific isoforms is a hallmark of the proteins. 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 regulatory mechanisms dictating expression patterns as well as specific functions of two of the soluble isoforms, HLA-G5 and HLA-G6, using newly developed recombinant HLA-G5 and -G6 and monoclonal antibodies to the proteins. In Project II, Petroff will examine the consequences of co-expression of HLA-G isoforms and members of the B7 family using stably transfected cells expressing various combinations of HLA-G/B7 proteins. In Project III, 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 collection, 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 certain types of 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. This research is highly relevant to public health. Approximately one in ten couples experiences fertility problems, and preterm labor is a common condition where pregnancy is terminated. Both conditions are costly in personal and financial terms.

描述（由申请人提供）：源自主要组织相容性复合体（MHC）Ib类基因HLA-G的糖蛋白首次在人胎盘中被描述，它们位于母体蜕膜内和邻近的细胞滋养层（CTB）细胞中。尽管进行了近二十年的深入研究，但这些蛋白质对半异体妊娠的贡献仍然知之甚少。 HLA-G基因具有许多新颖的特点：该基因在编码区含有少量多态性，但在调控区含有多种多态性；通过来自单个基因的 mRNA 的选择性剪接产生至少 7 个亚型；特定亚型的受限细胞和组织分布是蛋白质的标志。在该项目申请中，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。这三人，Joan Hunt 博士（堪萨斯州堪萨斯城堪萨斯大学医学中心）、来自同一机构的 Margaret Petroff 博士和 Carole Ober 博士（伊利诺斯州芝加哥市芝加哥大学）在生殖免疫学和生殖免疫学领域拥有丰富的经验。他们的大部分研究集中在妊娠期 MHC 抗原上。在项目 I 中，Hunt 将使用新开发的重组 HLA-G5 和 HLA-G6 以及针对这些蛋白质的单克隆抗体，研究决定表达模式的调控机制以及两种可溶性亚型 HLA-G5 和 HLA-G6 的特定功能。在项目 II 中，Petoff 将使用表达 HLA-G/B7 蛋白各种组合的稳定转染细胞来检查 HLA-G 同工型和 B7 家族成员共表达的后果。在项目 III 中，Ober 将使用新开发的等位基因特异性探针来研究 HLA-G 基因型的功能方面，并将探索与生育力下降的关系。该程序由两个核心支持。由 Hunt 领导的核心 A 管理部门将负责确保实验结果的收集、整合和发布。由 Ober 指导的 Core B 组织收集和基因分型将收集并向所有研究人员提供早期妊娠组织和来自某些类型问题妊娠的组织。该核心还将识别与每个项目相关的基因的多态性。该项目的研究人员完全期望，他们密切而系统的合作将构成一种强有力的方法，以阐明 HLA-G 表达、调节和功能的关键方面，并最终带来针对生育能力受损的新的和改进的疗法。这项研究与公共卫生高度相关。大约十分之一的夫妇遇到生育问题，早产是终止妊娠的常见情况。这两种情况对于个人和经济而言都是代价高昂的。