肾上腺素能受体信号在蜕膜发育与妊娠维持中的生理病理作用及分子机制研究

Reproductive health is the core connotation of population health, unexplained recurrent miscarriage seriously affects the physical and mental health of couples with childbearing age, and maternal stress factor is considered as an important risk factor for unexplained recurrent miscarriage. Decidual development is the key step for successful pregnancy. Adrenergic receptor signaling can be distributed in both human and mouse endometrium. However, the specific pathophysiological regulation mechanisms are poorly understood. Our previous work has found that adrenergic receptors expression of uterine stroma increased during early pregnancy, and exaggerated epinephrine-adrenergic receptor signaling impaired uterine decidualization, which may lead to pregnancy failure in mice, suggesting that adrenergic receptor signaling is important in the development of decidua and pregnancy. Based on this, the project intends to carry out the following research: (1) To confirm the expression pattern and role of each subtype of epinephrine receptor in the human endometrial stromal cells decidual development;(2) The potential molecular network of adrenergic receptors involved in regulating the development of decidualization;(3) Effect of abnormal activation or inhibition of adrenergic receptor signaling on decidual development and pregnancy maintenance; This study aims to comprehensively reveal the key role of human endometrial adrenergic receptor signaling in the development of decidua and pregnancy, and provide new theoretical guidance for pregnancy failure caused by stress factors.

生殖健康是人口健康的核心内涵，不明原因反复流产严重困扰育龄夫妇的身心健康，精神紧张性因素被认为是不明原因反复流产的重要危险因素。蜕膜发育是决定妊娠成功的关键环节，肾上腺素能受体信号在人和小鼠子宫内膜均有分布，然而具体病理生理调控机制知之甚少。申请人在前期的研究中已发现小鼠子宫蜕膜细胞肾上腺素能受体表达逐渐增高，其信号过度激活会使蜕膜细胞功能受损，进而导致小鼠妊娠失败，提示肾上腺素能受体信号在蜕膜发育及妊娠维持具重要意义。基于此，本项目拟开展如下研究：（1）确认肾上腺素能受体各亚型在人子宫内膜基质细胞蜕膜发育过程中的表达模式及作用；（2）肾上腺素能受体参与调控蜕膜发育的潜在信号分子网络；（3）肾上腺素能受体信号的异常激活或阻断对蜕膜发育及妊娠维持的影响；本研究旨在全面揭示人子宫内膜肾上腺素能受体信号对蜕膜发育及妊娠维持的关键作用，为临床上紧张因素造成的妊娠失败提供新的理论指导。

生殖健康是人口健康的核心内涵，不明原因反复流产严重困扰育龄夫妇的身心健康，精神紧张性因素被认为是不明原因反复流产的重要危险因素。蜕膜发育是决定妊娠成功的关键环节，肾上腺素能受体信号在人和小鼠子宫内膜均有分布，然而具体病理生理调控机制知之甚少。申请人在前期的研究中已发现小鼠子宫蜕膜细胞肾上腺素能受体表达逐渐增高，其信号过度激活会使蜕膜细胞功能受损，进而导致小鼠妊娠失败，提示肾上腺素能受体信号在蜕膜发育及妊娠维持具重要意义。基于此，本项目开展了如下研究：（1）确认肾上腺素能受体各亚型在人子宫内膜基质细胞蜕膜发育过程中的表达模式及作用；（2）肾上腺素能受体参与调控蜕膜发育的潜在信号分子网络；（3）肾上腺素能受体信号的异常激活或阻断对蜕膜发育及妊娠维持的影响；实验结果提示：生理情况下，肾上腺素能信号可通过ADRA2C/AKT/FOXO1信号途径，参与子宫内膜接受态的建立，有利于早期正常妊娠；外源性和内源性肾上腺素水平增高均会改变下游信号转导，损害子宫内膜基质细胞蜕膜分化，影响子宫内膜接受态功能导致早期妊娠失败。本研究旨在全面揭示人子宫内膜肾上腺素能受体信号对蜕膜发育及妊娠维持的关键作用，为临床上紧张因素造成的妊娠失败提供新的理论指导。