转录因子Rbpj-κ及巨噬细胞在小鼠子宫内膜损伤后修复和重建过程中的作用

Mammalian endometrium, especially in primates, suffers injury after each menstruation, parturition and some pathological conditions. Well repair of the injury and the regeneration of endometrium are crucial for the implantation of embryo and pregnancy in the next cycle. So far, there are only few published studies focused on this essential process. The mechanisms of endometrium repair and regeneration are still unclear. Our previous data have showed that lack of Rbpj-κ, the core transcription factor of canonical Notch signaling pathway in mouse uterus results in significantly impaired endometrium postpartum repair, associates with unbalanced M1/M2 macrophage polarization, and further leads to secondary infertility. However, the detail mechanisms under the regulation of Rbpj-κ on macrophage polarization and how does M1/M2 macrophage polarization contribute to endometrium repair are still not quite clear. In present study, we are going to further investigate the key role of Rbpj-κ-INFγ-M1/M2 macrophages axle during the process of endometrium repair and regeneration after injury, by using Pgr-Cre driven uterine specific Rbpj (gene that encodes Rbpj-κ) knock out transgenic tool and endometrium damage models that induced by pregnancy-parturition or artificial mouse menstruation. The consequences of this study will broaden our horizon to understand the molecular mechanisms of this all-important process, provide research bases positive impact for improvement of domestic animal reproduction and new therapies for women reproductive disease.

哺乳动物特别是灵长类的子宫内膜在每次月经、分娩后以及某些病理状态下会受到损伤，损伤的修复及内膜的重建是确保下一次妊娠的重要前提。目前只有少数的研究关注这一重要的生理过程，其内膜修复和重建过程的机理还不明确。我们的前期研究结果表明，缺失转录因子Rbpj-κ的小鼠子宫内膜产后修复过程存在明显缺陷，并伴随着M1/M2型巨噬细胞极化的失衡以及继发性不孕。但是，这一过程的内在机制尚不明确。在本研究中，我们将以“Rbpj-κ及巨噬细胞极化在小鼠子宫内膜损伤后修复和内膜重建过程中的作用机理”为关键科学问题，使用子宫特异性敲除Rbpj基因的工具鼠和小鼠的妊娠（产后）损伤和人造月经模型，进一步探索并证实Rbpj-κ-INFγ-M1/M2型巨噬细胞这条通路对子宫内膜修复和重建过程中的重要作用。本研究的结果将有助于了解子宫损伤后修复和内膜重建的机理和分子机制，为提高动物的繁殖率治疗人类生殖疾病等提供理论依据。

哺乳动物生殖系统是关乎物种繁衍的重要器官的集合。在灵长类，子宫内膜在每次月经、分娩后以及某些病理状态下会受到损伤，损伤的修复及内膜的重建是确保下一次妊娠的重要前提。此外，诸如内膜炎、阴道炎以及子宫内膜异位症等疾病也严重影响了雌性哺乳动物，特别是人类女性的生殖能力和生殖健康。本课题利用基因工程鼠，通过敲除Rbpj或者过表达Notch1胞内结构域N1ICD的形式对Notch信号通路进行干扰，并在构建的多种疾病模型上研究了该信号通路对雌性生殖道的影响。我们证实：1）开放饲养条件下，Pgrcre/+ RbpjF/F小鼠损伤后的子宫角会发生严重的炎症反应，并伴随着一定程度的化脓；2）缺失Rbpj影响小鼠阴道上皮的更新及阴道的自净能力，进而造成细菌的大量潴留，引发阴道炎和内膜炎；3）缺失Rbpj造成小鼠子宫内膜对孕酮的反应能力下降和蜕膜化障碍；4）Notch信号通路通过其经典路径促进子宫内膜异位症的发生。本研究的结果有助于了解子宫损伤后修复和内膜重建的生理机理和分子机制，以及生殖道炎症和子宫内膜异位症等疾病的发病机制，为提高动物的繁殖率治疗人类生殖疾病等提供理论依据。本课题共发表高水平论文6篇，其中5篇发表在英文SCI期刊上，1篇发表在中文核心期刊上。培养博士2人、硕士7人以及本科毕业生1人。已经完成计划任务书中所要求的各项研究任务。