HLA-G at the Maternal Fetal Interface

母胎界面的 HLA-G

• 批准号: 7179574
• 负责人: JOAN Sherar HUNT
• 金额: $ 92.2万
• 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/7179574
• 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的糖蛋白首先在人胎盘中描述，它们位于母体蜕膜内和附近的细胞滋养层（CTB）细胞中。尽管近二十年的深入研究，这些蛋白质的贡献半同种异体妊娠仍然知之甚少。HLA-G基因具有许多新的特征：该基因在编码区含有很少的多态性，但在调控区含有多个多态性;至少7种异构体是由来自单个基因的mRNA的选择性剪接产生的;特定异构体的有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。Joan Hunt博士（堪萨斯大学医学中心，堪萨斯城，堪萨斯州）、Margaret Petroff博士（来自同一机构）和Carole Ober博士（芝加哥大学，芝加哥，伊利诺伊州）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HLA-G5和HLA-G6以及针对蛋白质的单克隆抗体，研究决定表达模式以及两种可溶性亚型HLA-G5和HLA-G6的特定功能的调控机制。在项目II中，Petroff将使用表达HLA-G/B7蛋白的各种组合的稳定转染细胞来检查HLA-G同种型和B7家族成员的共表达的后果。在项目III中，Ober将使用新开发的等位基因特异性探针研究HLA-G基因型的功能方面，并将探索与生育能力下降的关系。该计划由两个核心支持。核心A。由Hunt领导的管理部门将负责确保收集、整合和公布实验结果。由Ober指导的核心B组织收集和基因分型将收集并向所有研究者提供早期妊娠组织和某些类型的问题妊娠组织。该核心还将确定与每个项目相关的基因多态性。该项目的研究人员完全期望他们的密切和系统的合作将构成一种强有力的方法来阐明HLA-G表达，调节和功能的关键方面，并最终导致新的和改进的治疗生育能力受损的方法。这项研究与公共卫生密切相关。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。这两种情况在个人和财政方面都是昂贵的。