子宮重朔的發生是為了適應懷孕過程中胚胎的持續發育。在懷孕的末期，子宮腔室的變大則是與子宮壁變薄和子宮活動力下降有關。同時，雌激素在懷孕末期也達到最大濃度。此外，兩種雌激素受體(ERα 與ERβ)的表現也與懷孕有關。因此，本篇研究之目的在於探討雌激素受體貝它(ERβ)在懷孕子宮裡所扮演的角色。
我們第一個目標是建立透過次細胞分離懷孕第十八天(G18)大鼠子宮的蛋白質體分析資料庫，而這份蛋白清單讓我們能夠假設子宮重朔是由於細胞骨架，胞外基質與PKA-mediated的途徑相關的蛋白發生變化而成型。西方墨點法的結果顯示相較於懷孕第7天SMMHC, α actin, β actin, nucleolin, α2-macroglobulin, 和 Bcl-xL是在懷孕第18天的子宮有較高的表現量，然而fibronectin, collagen VI, TH, PKAIIRα 和prohibitin 則是在第18天子宮的表現量較低，另外integrinβ1, VDAC-1, Ras, 和 Src均無差異在第7與第18天的子宮。我們更進一步分析cAMP對子宮收縮的影響。這些結果推論出懷孕末期的子宮具有細胞肥大，胞外基質崩解伴隨的子宮壁變薄和氧化自由基造成的細胞凋亡。而在懷孕末期子宮的交感神經阻斷可能會造成子宮對cAMP的敏感度增加並且有助於子宮靜默。
第二個目標則是量化出ERβ 活化劑genistein能夠調控出的蛋白。ERβ具有較高的表現在G18，指出懷孕末期雌激素的作用大多被ERβ所操控著。利用定量蛋白質體定出159個蛋白。根據這份清單，我們假設genistein可以透過破壞蛋白酶和蛋白酶抑制劑的平衡來達到子宮重朔。這種失去平衡可能導致胞外基質以及細胞骨架蛋白的分解。西方墨點法的結果顯示 10-9M genistein 使得α2-macroglobulin, collagen VI, fibronectin, Bcl-xL, α actin 和 α tubulin 下降。Genistein甚至抑制了細胞存活與子宮收縮。而西方墨點法和功能性分析結果也都支持我們的假說。
總結來說，雖然ERβ高度表現在懷孕的子宮中，但是其功能仍有大部分尚未釐清。本研究提供了ERβ可能扮演的重要角色，尤其是在懷孕子宮外觀與功能的重朔，而這是透過改變蛋白酶和蛋白酶抑制劑的平衡。我們也發現ERβ的新角色可以當作避免早產的治療。

To accommodate the growing embryo, uterine remodeling occurs. During late-gestation, uterine enlargement is associated with wall thinning and uterine quiescence in late pregnancy. Correspondingly, the estrogen level continuously rises to the maximal level in late-gestation. Since the expression of two estrogen receptors (ERα and ERβ) is gestation-dependent, the purpose of this study was to explore the possible role of ERβ in pregnant uteri.
Our first objective was to establish a database of uterine proteome by subcellular fractionation coupled proteomic analysis of rat uteri on gestation day 18 (G18). The list of uterine proteins from late-gestation uteri allowed us to hypothesize that alteration in the abundance of proteins related to cytokskeleton, extracellular matrix (ECM), and PKA-mediated pathways contributed to uterine remodeling. Western blotting analysis showed that expression of SMMHC, α actin, β actin, nucleolin, α2-macroglobulin, and Bcl-xL were higher in G18 uteri than in G7. The expression of fibronectin, collagen VI, TH, PKAIIRα and prohibitin was lower in G18 uteri than in G7. The expression of integrinβ1, VDAC-1, Ras, and Src was indifferent between G18 and G7 uteri. Contraction analysis was to further examine the influence of cAMP on uterine contractions. These data suggested the presence of cellular hypertrophy and wall thinning with ECM degradation and ROS-induced apoptosis. Sympathetic denervation in late pregnant uteri may increase the sensitivity of late-gestation uteri to cAMP, which contributes to uterine quiescence.
The second objective was to quantify the proteins modulated by genistein, an ER activator. Higher expression of ERβ in G18 than in G7 suggests that the estrogenic action in the late pregnancy was mainly determined by ERβ. Repeated quantitative proteomic approaches had identified 159 proteins in 14 bands. The list of the proteins modulated by genistein allowed us to hypothesize that genistein caused uterine remodeling by disturbing the balance between proteases and protease inhibitors. The imbalance may contribute to the reduction of ECM and cytoskeletal proteins. Western blotting showed the reduction of protease inhibitors, such as 2-macroglobulin. Correspondingly, the expression of collagen VI, fibronectin, Bcl-xL, α actin and α tubulin were decreased by genistein at 10-9M. Even cell survival and uterine contraction were suppressed by genistein. Both Western blotting and functional assays supported our hypothesis.
In conclusion, although ERβ is highly expressed in pregnant uteri, its role in pregnant uteri is largely unknown. This study provides an insight that ERβ plays an important role in morphological and functional remodeling of pregnant uteri by shifting the balance between proteases and protease inhibitors. The novel role of ER may serve as an alternative remedy for preterm labor.

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