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Study of the mechanisms underlying the salutary effects of Heme Oxygenase-1 in implantation, placentation and fetal growth using a mouse model and in vitro approaches. Participation of carbon monoxide in the preparation of the murine uterine microenvironm

使用小鼠模型和体外方法研究血红素加氧酶 1 对着床、胎盘和胎儿生长的有益作用的机制。

基本信息

批准号：
277699676
负责人：
Professorin Dr. Ana Claudia Zenclussen
金额：
--
依托单位：
Department Umweltimmunologie und Core Facility Studien
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/277699676?language=en
关键词：
Study mechanisms underlying salutary effects

项目摘要

Normal pregnancy is a physiological state characterized by the occurrence of different processes taking place at different stages, each of them unique. Pregnancy begins with the fertilization of the ovum, followed by implantation of the blastocyst in the maternal uterus. To implant, the blastocyst needs to adhere to the endometrium so that it can be provided with oxygen and nutrients. For these dramatic changes to occur, tissue remodeling and inflammatory processes in the uterus are required. However, the ablation of immunosuppressive molecules is detrimental, so that it can be assumed that both, inflammatory and anti-inflammatory pathways are required. Heme oxygenase (HO) is a ubiquitous enzyme that catalyzes the initial and rate limiting step in the oxidative degradation of heme to bilirubin. CO and biliverdin, both generated via the catabolism of heme by the isoform HO-1, are potent immunosupressors which induce tolerance against allografted organs. We have recently shown that HO-1 is critical for pregnancy success as it determines implantation, placentation and intrauterine fetal survival. This is mainly mediated by the HO-1 metabolite CO. After implantation occured and while placentation is taking place, a period of immune tolerance must exist that allows the half-foreign embryo to grow without being attacked by the maternal immune system. HO-1 modulates the maternal immune system to allow tolerance towards the growing fetus by affecting the function of dendritic cells and regulatory T cells. HO-1 is therefore a central regulator of pregnancy as it critically interferes with the important steps of implantation, placentation, embryonic and fetal development and immune tolerance. Thus, the study of mechanisms underlying HO-1-protective functions during pregnancy is clinically very relevant. The present project deals with HO-1-associated mechanisms that allow implantation to occur and focuses on the HO-1-modulated changes in the uterine microenvironment that are necessary for the embryo to implant and grow. The project further aims to determine the importance of HO-1 and CO in allowing a proper blood flow that ensures a correct placentation and fetal support.

正常妊娠是一种生理状态，其特征是在不同阶段发生不同的过程，每个过程都是独特的。妊娠开始于卵子受精，随后胚泡植入母体子宫。为了植入，胚泡需要粘附在子宫内膜上，以便为它提供氧气和营养。为了发生这些巨大的变化，需要子宫内的组织重塑和炎症过程。然而，免疫抑制分子的消融是有害的，因此可以假设需要炎症和抗炎途径两者。血红素加氧酶（HO）是一种普遍存在的酶，催化血红素氧化降解为胆红素的起始和限速步骤。CO和胆绿素，都是通过血红素的异构体HO-1的催化作用产生的，是有效的免疫抑制剂，诱导对同种异体移植器官的耐受。我们最近发现HO-1对妊娠成功至关重要，因为它决定了着床、胎盘形成和宫内胎儿存活。这主要是由HO-1代谢产物CO介导的。在着床发生后，当胎盘形成时，必须存在一段免疫耐受期，使半外来胚胎在不受母体免疫系统攻击的情况下生长。HO-1通过影响树突状细胞和调节性T细胞的功能来调节母体免疫系统以允许对生长中的胎儿的耐受。因此，HO-1是妊娠的中心调节因子，因为它严重干扰着床、胎盘形成、胚胎和胎儿发育以及免疫耐受的重要步骤。因此，研究HO-1在妊娠期间的保护功能的机制在临床上非常重要。本项目涉及HO-1相关的机制，使植入发生，并侧重于HO-1调节的子宫微环境的变化，这是胚胎植入和生长所必需的。该项目进一步旨在确定HO-1和CO在允许适当的血流以确保正确的胎盘形成和胎儿支持方面的重要性。