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Dysregulated CD74 in macrophage-trophoblastic interactions and the pathogenesis of preeclampsia

巨噬细胞-滋养层相互作用中 CD74 失调和先兆子痫的发病机制

基本信息

批准号：
195146839
负责人：
Privatdozent Dr. Florian Herse
金额：
--
依托单位：
Max-Delbrück-Centrum für Molekulare Medizin (MDC) in der Helmholtz-Gemeinschaft
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/195146839?language=en
关键词：
Dysregulated CD74 macrophage trophoblastic interactions

项目摘要

A better understanding of pathophysiologic mechanisms that lead to the development of preeclampsia is essential to develop new strategies for the prevention and the treatment. Trophoblastic activity and invasion are crucial to placental development; aberrancies in this process could lead to a pathological pregnancies and preeclampsia. Placental macrophages, the Hofbauer cells, regulate trophoblastic activity and direct or indirect contact between both cell types is essential for successful pregnancy. In preliminary work, we showed that the cluster of differentiation 74 (CD74) is downregulated in the preeclamptic placenta and localized CD74 in macrophages. Furthermore, downstream target factors of CD74 were also suppressed in the preeclamptic placenta. We propose that CD74 is involved in the development of preeclampsia and is a potential candidate for controlling cell-cell interaction between trophoblasts and macrophages. Thus, studies on CD74 and the macrophage-trophoblast interaction in pregnancy and preeclampsia are essential to enhance our knowledge of its modes of action and to evaluate its potential as a therapeutic agent in preeclampsia. Our global hypothesis is that a downregulated CD74 expression in placental macrophages is an underlying pathologic mechanism leading to preeclampsia. Specifically, we will pursue the following objectives: Objective 1:We will determine the underlying mechanisms of CD74 downregulation in the preeclamptic placenta. Objective 2:We will investigate the functional consequence of the CD74 downregulation on the macrophage-trophoblast interaction. Objective 3:We will determine the consequence of a CD74 downregulation in an animal model.Innovation:We will be the first to reveal the impact of CD74 in the macrophage-trophoblast interaction and the pathogenesis of preeclampsia, respectively. Our findings could lead to new mechanistic and therapeutic avenues for this devastating disease.

更好地了解导致先兆子痫发展的病理生理机制对于制定预防和治疗的新策略至关重要。滋养层细胞的活动和侵入对胎盘发育至关重要;这一过程中的异常可能导致病理性妊娠和先兆子痫。胎盘巨噬细胞，霍夫鲍尔细胞，调节滋养层细胞的活动和两种细胞类型之间的直接或间接接触是成功怀孕所必需的。在前期工作中，我们发现分化簇74（CD 74）在先兆子痫胎盘中下调，并在巨噬细胞中定位CD 74。此外，CD 74的下游靶因子在先兆子痫胎盘中也受到抑制。我们认为CD 74参与了先兆子痫的发生，是控制滋养层细胞和巨噬细胞之间细胞间相互作用的潜在候选者。因此，研究CD 74和巨噬细胞-滋养层细胞在妊娠和先兆子痫的相互作用是必不可少的，以提高我们的知识，其作用模式，并评估其作为先兆子痫的治疗剂的潜力。我们的总体假设是胎盘巨噬细胞中下调的CD 74表达是导致先兆子痫的潜在病理机制。具体而言，我们将追求以下目标：目标1：我们将确定潜在的机制，CD 74下调先兆子痫胎盘。目的2：探讨CD 74下调对巨噬细胞-滋养细胞相互作用的影响。目的3：我们将确定在动物模型中CD 74下调的后果。创新：我们将是第一个揭示CD 74在巨噬细胞-滋养层相互作用和先兆子痫发病机制中的影响。我们的发现可能会为这种毁灭性疾病带来新的机制和治疗途径。