PROJECT 2 - Cell Signals in Ovulation and Lutenization

子宫内膜异位症通常与生育能力受损、卵巢功能改变和卵子发育不良有关。 质量。不断增加的内分泌和临床数据表明急性期基因(如CEBPB)和 在正常情况下，炎性细胞因子(如IL6)在包括卵巢细胞在内的非免疫细胞中诱导 在发育过程中，它们在基因表达谱和基因表达谱中施加细胞上下文特定的变化 细胞功能。因此，炎性细胞因子/趋化因子的不受控制的表达有可能 改变正常卵巢功能，并可能介导细胞因子升高和 与子宫内膜异位症相关的趋化因子。这一观点得到了最近的观察的支持，即卵巢 体细胞在正常排卵过程中产生强大的细胞因子，而IL-6等细胞因子 影响颗粒细胞内分泌功能，调节卵丘细胞基质形成活动 围绕着排卵的卵母细胞。细胞因子也可能调节戏剧性的基因重新编程， 引导颗粒细胞向终末分化的黄体细胞的转变，这一过程涉及 产生特定的细胞因子，细胞周期停滞和终末细胞分化。CEBPp(CAAT增强器 结合蛋白β)与急性期反应和细胞周期停滞有关。CEBPp还可以影响 116的表达。在卵巢中，CEBPp在小鼠、大鼠和猪的颗粒细胞中被诱导 促黄体生成素/人绒毛膜促性腺激素排卵前卵泡。CEBPB为空的小鼠无法排卵或黄体生成。然而，生化 CEBPp调节这些卵巢事件的分子机制尚不清楚。因此， 我们认为IL6(和/或其他细胞因子)和CEBPp的表达变化介导了关键事件 与排卵和黄体化有关，当细胞因子过多时，可能会导致受损 子宫内膜异位症患者的卵巢细胞反应。具体目标一：确定归纳和处理的模式 未成熟小鼠卵泡颗粒和卵丘细胞中CEBPp的激活(磷酸化) 排卵和黄体生成。具体目标二：确定影响排卵的C/EBPp指标与 利用CEBPB条件基因敲除小鼠控制颗粒细胞向黄体细胞的终末分化。 特定目标III：确定CEBPp、IL6和特异性细胞因子和趋化因子与临床的相关性 子宫内膜异位症患者和子宫内膜异位症小鼠模型中卵巢细胞功能受损。

Endometriosis is frequently associated with impaired fertility, altered ovarian function and poor oocyte quality. Increasing endocrine and clinical data indicate that acute phase genes (such as Cebpb) and inflammatory cytokines (such as IL6) are induced in non-immune cells, including ovarian cells during normal processes of development where they exert cell context specific changes in gene expression profiles and cell function. Therefore, uncontrolled expression of inflammatory cytokines/chemokines has the potential to alter the normal ovarian function and may mediate the pleotrophic consequences of elevated cytokines and chemokines associated with endometriosis. This notion is supported by the recent observations that ovarian somatic cells produce potent cytokines during the normal process of ovulation and that cytokines such as IL6 impact the endocrine functions of granulosa cells and regulate the matrix forming activities of cumulus cells surrounding the ovulated oocyte. Cytokines may also regulate the dramatic genetic reprogramming that directs the transition of granulosa cells to terminally differentiated luteal cells, a process that involves a production of specific cytokines, cell cycle arrest and terminal cell differentiation. CEBPp (CAAT enhancer binding protein beta) is linked to acute phase responses as well as cell cycle arrest. CEBPp can also impact the expression of 116. In the ovary CEBPp is induced in granulosa cells of mouse, rat and porcine preovulatory follicles by LH/hCG. Mice null for Cebpb fail to ovulate or luteinize. However, the biochemical and molecular mechanisms by which CEBPp regulates these ovarian events remains unknown. Therefore, we propose that altered expression of IL6 (and/or other cytokines) and CEBPp mediate critical events associated with ovulation and luteinization and when in excess cytokines could contribute to the impaired ovarian cell responses in patients with endometriosis. Specific Aim I: Determine the pattern of induction and activation (phosphorylation) of CEBPp in granulosa and cumulus cells of follicles of immature mice induced to ovulate and luteinize. Specific Aim II: Determine targets of C/EBPp that impact ovulation versus those that control the terminal differentiation of granulosa cells to luteal cells using Cebpb conditional knockout mice. Specific Aim III: Determine the clinical relevance of CEBPp, IL6 and specific cytokines and chemokines to impaired ovarian cell function in patients with endometriosis and in mouse models of endometriosis.