Induction of decidualization of endometrial stromal cells as a therapeutical approach for the treatment of endometriosis

子宫内膜异位症的特征是子宫内膜组织异位，并导致严重的腹痛和生育能力低下。此外，目前的医学治疗与不期望的副作用和高复发率相关。由于子宫内膜间质细胞在这种疾病的发生中起着关键作用，并且这些细胞的终末分化（蜕膜化）已被证明在子宫内膜异位症患者中受损，因此异位子宫内膜间质细胞的蜕膜化诱导可能是创新治疗方法的有希望的靶点。因此，本课题的目的是寻找子宫内膜异位症患者子宫内膜间质细胞蜕膜化和凋亡的潜在诱导因子。基于孕酮受体途径以及cAMP介导的信号传导参与诱导蜕膜化的发现，将分析与这些途径相互作用的化合物诱导患有和不患有子宫内膜异位症的妇女的子宫内膜基质细胞分化的潜力。将使用两个研究组的子宫内膜基质细胞的原代培养物在体外评价有效化合物和化合物组合。此后，将在子宫内膜异位症小鼠模型中评价最有前途的药物在体内诱导异位子宫内膜病变蜕膜化的潜力。将通过形态学参数和蜕膜化标志物催乳素的定量评价对蜕膜化的相应影响。此外，将分析这些化合物对增殖、凋亡和血管生成的影响。所测试的化合物在诱导蜕膜化和病变消退方面的效力将与单个患者的子宫内膜的受体状态相关，目标在于开发个体化治疗方法。

Endometriosis is characterized by the presence of endometrial tissue in ectopic locations and leads to severe abdominal pain and subfertility. Moreover, current medical treatment is associated with undesirable side effects and high recurrence rates. Since endometrial stromal cells play a pivotal role in the establishment of this disease, and terminal differentiation (decidualization) of these cells has been shown to be impaired in endometriosis patients, induction of decidualization of ectopic endometrial stromal cells may be a promising target for innovative therapeutical approaches. Thus the aim of the project is to discover potential inductors of decidualization and apoptosis of endometrial stromal cells of endometriosis patients. Based on the finding that the progesterone receptor pathway as well as cAMP-mediated signalling is involved in induction of decidualization, compounds interacting with these pathways will be analyzed in regard to their potential to induce differentiation of endometrial stromal cells from women with and without endometriosis. Effective compounds and compound combinations will be evaluated in vitro using primary culture of endometrial stromal cells of both study groups. Thereafter, the most promising agents will be evaluated in an endometriosis mouse model in regard to their potential to induce decidualization of ectopic endometrial lesions in vivo. The respective effect on decidualization will be evaluated by morphologic parameters and by quantification of the decidualization marker prolactin. Moreover, the effect of these compounds on proliferation, apoptosis, and angiogenesis will be analyzed. The potency of the compounds tested on induction of decidualization and regression of lesions will be correlated to the receptor status of the endometrium of single patients, targeting on the development of individualized therapeutical approaches.