MOLECULAR REGULATION OF LUTEAL FUNCTION

黄体产生的黄体孕酮对子宫内膜的植入和维持妊娠至关重要。最近的研究表明，尽管大鼠黄体中缺乏孕酮受体，但孕酮也可以通过内分泌机制作用于黄体细胞，维持自身的分泌。信号通过糖皮质激素受体发生。孕激素受体的缺失令人费解，因为这一基因的表达是由雌二醇增加的，而且由于大鼠黄体产生雌二醇，表达雌激素受体，并对雌二醇高度反应。参与这项研究的两个实验室进行的研究表明，孕酮通过阻止至少两种基因产物的表达来维持自身的生产：20α-羟基类固醇脱氢酶，一种分解孕酮的酶；以及白细胞介素6，一种不利于类固醇生成的细胞因子。这项建议的总体目的是：1)确定黄体中孕酮受体沉默的原因；2)研究孕酮下调黄体20α-羟基类固醇脱氢酶表达的分子机制；3)确定黄体中孕酮抑制IL-6表达是否涉及核因子-kappaB(NF-kappaB)家族转录因子。

The production of progesterone by the corpus luteum is crucial to prepare the endometrium for implantation and for the maintenance of pregnancy. Recent investigations have revealed that progesterone can acts also in luteal cells to sustain its own production through an intracrine mechanism, despite the lack of progesterone receptor in the rat corpus luteum. Signaling occurs through the glucocorticoid receptor. The lack of progesterone receptor is puzzling since the expression of this gene is increased by estradiol, and since the rat corpus luteum produces estradiol, expresses estrogen receptors, and is highly responsive to estradiol. Studies performed in both laboratories involved in the proposed study, have demonstrated that progesterone sustains its own production by preventing the expression of at least two gene products: 20alpha-hydroxysteroid dehydrogenase, an enzyme which catabolizes progesterone; and interleukin-6, a cytokine detrimental for steroidogenesis. The overall aims of this proposal are: 1) to determine the reason by which the progesterone receptor is silenced in the rat corpus luteum; 2) to examine the molecular mechanisms whereby progesterone down regulates the expression of luteal 20alpha- hydroxysteroid dehydrogenase; and 3) to determine whether the inhibition of interleukin-6 expression by progesterone in the corpus luteum involves the nuclear factor kappa-B (NF-kappaB) family of transcription factors.