Regulation of Luteal Function

描述（由申请方提供）：妊娠的建立和维持需要黄体（CL）功能的协调激素调节。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PRL信号通过PRL受体的短形式（PRLRS）对卵巢产生严重影响，导致卵泡变性和卵巢早衰。由于我们观察到PRL缺失小鼠卵巢中PRLRS的表达导致Foxo 3a和GALT的抑制，这两种蛋白的缺失/突变导致类似的卵巢早衰，因此我们建议在第一个具体目标中确定PRL是否通过PRLRS起作用阻止Foxo 3a的表达，Foxo 3a通常刺激GALT转录活性。Foxo 3的缺乏导致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中的半乳糖毒性和细胞死亡。我们还发现PRLRS与一种新发现的负责CL中E合成的酶（我们命名为PRAP/17 BHSD-7）相关，并且当被PRL激活时，引起该酶的磷酸化。这是第一次证明膜结合受体与类固醇生成酶的直接缔合可以导致酶磷酸化。该关联还可以防止通过PRLRS的PRL信令。这种磷酸化的意义，以及PRAP/17 aHSD-7在黄体E产生中的重要性，其调节及其在维持妊娠中的作用将使用我们提出产生的细胞系和PRAP/17 aHSD-7缺失小鼠来研究。

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.