Regulation of Luteal Function

描述（申请人提供）：妊娠的建立和维持需要黄体（CL）功能的激素协调调节。我们实验室的广泛研究已经确定了雌二醇(E)和催乳素（PRL）的作用和相互作用，并导致最近发现通过PRL受体（PRLRS）的短形式的PRL信号传导对卵巢有严重影响，导致卵泡变性和卵巢早衰。由于我们观察到PRLRS在PRL缺失小鼠卵巢中的表达导致Foxo3a和GALT的抑制，这两种蛋白的缺失/突变导致类似的卵巢早衰，我们在第一个具体目的中提出确定PRL是否通过PRLRS作用阻止Foxo3a的表达，而Foxo3a通常会刺激GALT的转录活性。Foxo3的缺失导致GALT的抑制和半乳糖及其代谢物的增加，导致颗粒和卵母细胞的半乳糖毒性和细胞死亡。我们还发现，PRLRS与PRL结合，当PRL激活时，导致一种新发现的负责CL中E合成的酶的磷酸化，我们将其命名为PRAP/17BHSD-7。这是首次证明膜结合受体与甾体生成酶的直接结合可导致酶磷酸化。这种关联也可能阻止PRL通过PRLRS发出信号。这种磷酸化的意义，以及PRAP/17aHSD-7在黄体E产生、调节及其在妊娠维持中的作用，将在细胞系和我们拟产生的PRAP/17aHSD-7缺失小鼠中进行研究。

DESCRIPTION (provided by applicant): The establishment and maintenance of pregnancy requires the coordinated hormonal regulation of corpus luteum (CL) function. Extensive investigations from our laboratory have defined the action and interaction of estradiol (E) and prolactin (PRL) and have led to the recent discovery that PRL signaling through the short form of the PRL receptor (PRLRS) has a severe impact on the ovary, causing follicular degeneration and premature ovarian failure. Because of our observation that the expression of PRLRS in the ovaries of PRL null mice leads to inhibition of Foxo3a and GALT, 2 proteins whose deletion/mutation causes similar premature ovarian failure, we propose in the first specific aim to determine whether PRL acting through PRLRS prevents the expression of Foxo3a which normally stimulates GALT transcriptional activity. Absence of Foxo3 then leads to inhibition of GALT and an increase in galactose and its metabolites, causing galactose toxicity and cell death in granulosa and oocytes. We have also discovered that PRLRS associates with and, when activated by PRL, causes the phosphorylation of a newly discovered enzyme responsible for E synthesis in the CL that we named PRAP/17BHSD-7. This is the first demonstration that direct association of a membrane bound receptor with a steroidogenic enzyme can lead to enzyme phosphorylation. This association may also prevent PRL signaling through PRLRS. The significance of such phosphorylation, and the importance of PRAP/17aHSD-7 in luteal E production, its regulation and its role in the maintenance of pregnancy will be investigated using both cell lines and PRAP/17aHSD-7 null mice that we propose to generate.