HLA-G at the Maternal Fetal Interface

描述(申请人提供)：来源于主要组织相容性复合体(MHC)Ib类基因的糖蛋白，人类白细胞抗原-G首先在人类胎盘中被发现，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20年的密集研究，但这些蛋白质对半异基因妊娠的作用仍然知之甚少。人类白细胞抗原-G基因有许多新的特点：该基因在编码区有很少的多态性，但在调控区有多个多态性；至少有7个亚型是由来自单个基因的mRNA的选择性剪接产生的；特定的亚型在细胞和组织中的分布受限是蛋白质的一个标志。在这项计划申请中，来自两个机构的三名研究人员提议研究胎盘人类白细胞抗原-G在妊娠中的作用。这三人，琼·亨特博士(堪萨斯城堪萨斯城大学医学中心)、同一机构的玛格丽特·彼得罗夫博士和卡罗尔·奥贝尔博士(伊利诺伊州芝加哥大学)在生殖免疫学方面都有丰富的经验，他们的大部分研究都集中在怀孕期间的MHC抗原上。在项目I中，Hunt将使用新开发的重组人类白细胞抗原-G5和-G6以及针对这两种蛋白质的克隆抗体，研究决定两种可溶性亚型--人类白细胞抗原-G5和人类白细胞抗原-G6的表达模式和特定功能的调控机制。在第二个项目中，Petroff将使用稳定表达不同组合的HLA-G/B7蛋白的细胞来研究人类白细胞抗原-G亚型和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人类白细胞抗原-G基因的功能方面，并将探索与生育力下降的关系。该程序由两个内核支持。核心A.由亨特领导的行政部门将负责确保实验结果的收集、整合和发布。核心B组织收集和基因分型，由Ober指导，将收集和提供所有研究人员的早期妊娠组织和某些类型的问题妊娠的组织。该核心还将确定与每个项目相关的基因的多态。该项目的研究人员充分预计，他们密切和系统的合作将包括一种强大的方法来阐明人类白细胞抗原-G的表达、调节和功能的关键方面，并最终将导致针对生育力受损的新的和改进的治疗方法。这项研究与公共卫生高度相关。大约十分之一的夫妇经历生育问题，早产是终止妊娠的常见情况。这两个条件在个人和财务方面都代价高昂。

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.