Cell signaling in ovarian function

细胞是生命的单位。细胞可以作为单个实体或群体的一部分发挥作用。细胞对环境的适当反应不仅对细胞的生存至关重要，而且对细胞的生理作用也至关重要。细胞对激素刺激的反应涉及信号转导，通常包括环核苷酸作为关键参与者。近几十年来，环腺苷单磷酸（cAMP）比环鸟苷单磷酸（cGMP）得到了更多的研究。在卵巢中，cAMP对促卵泡激素（FSH）、促黄体生成素（LH）的响应已被表征，并研究了其在类固醇生成中的作用，但cGMP在卵巢卵泡细胞中的作用如何？近年来，由于哺乳动物卵母细胞减数分裂恢复的抑制模型，cGMP的贡献得到了更多的关注。该模型提示cGMP主要由颗粒细胞和积云细胞响应c型利钠肽合成。颗粒细胞、卵丘细胞和卵母细胞之间通过间隙连接产生电生理合胞体，使cGMP从颗粒细胞扩散到卵母细胞，从而抑制卵母细胞磷酸二酯酶。这种酶抑制增加了卵母细胞内阻断减数分裂恢复的cAMP。然而，对cGMP在卵泡中的作用知之甚少。cGMP不太可能只是等待转移到卵母细胞。cGMP的目标是什么？cGMP的生理影响是什么？cGMP是否调节cAMP反应？该研究计划的长期目标是完善我们对卵巢卵泡不同生理反应中信号转导重要性的理解。由于cAMP介导FSH和LH反应如细胞分化，因此假设cGMP作为第二信使发挥主要生理作用，可能调节电生理合胞体的细胞分化。因此，除了cGMP在抑制卵母细胞减数分裂恢复中的作用外，它在卵泡细胞内的生理贡献是什么？短期目标是1)通过比较三个卵泡阶段来表征cGMP信号传导的分子机制；2)通过磷酸蛋白组的研究确定cGMP靶点；3)利用化学激动剂和抑制剂证明cGMP在调节卵巢功能中的生理参与。这个研究项目代表了目前关于在体外成熟过程中提高卵母细胞质量的知识的重大贡献。这将影响与雌性配子质量有关的新的生殖生物技术的发展，并导致猪肉工业所追求的遗传改进。最后，本研究项目评估了对奶牛等其他物种也有有益应用的基础信号。

The cell is the unit of life. A cell functions as a single entity or as part of a group. The appropriate response of a cell to its environment is of great importance, not only for cell's survival, but for performing a physiological role. The cell's response to hormonal stimulation involves signal transduction which often includes cyclic nucleotides as key players. In recent decades, cyclic adenosine monophosphate (cAMP) has become much more studied than cyclic guanosine monophosphate (cGMP). In the ovary, the contribution of cAMP has been characterized in response to follicle-stimulating hormone (FSH), luteinizing hormone (LH), and studied in steroidogenesis, but what about the role of cGMP in the cells of ovarian follicles? Over the past few years, the contribution of cGMP has gained more attention because of the inhibitory model of oocyte meiotic resumption in mammals. This model suggests that the cGMP is synthesized mainly by the granulosa and cumulus cells in response to the C-type natriuretic peptide. The electrophysiological syncytium created between granulosa cells, cumulus cells and the oocyte by gap junctions allows cGMP to diffuse from the granulosa cells to the oocyte, and consequently inhibits oocyte phosphodiesterase. This enzymatic inhibition increases intra-oocyte cAMP that blocks meiotic resumption. However, very little is known about the role of cGMP in ovarian follicles. It is unlikely that cGMP is only waiting to move to the oocyte. What does cGMP target? What are the physiological impacts of cGMP? Does cGMP modulate cAMP response? The long-term objective of the proposed research program is to refine our understanding of the importance of signal transduction in the different physiological responses of the ovarian follicles. Since cAMP mediates FSH and LH responses such as cellular differentiation, the hypothesis is that cGMP plays a major physiological role as a second messenger, possibly modulating the cellular differentiation of the electrophysiological syncytium. Therefore, aside from the role of cGMP in the inhibition of oocyte meiotic resumption, what is its physiological contribution within the cells of the ovarian follicle? The short-term objectives are to 1) characterize the molecular machinery involved in cGMP signaling by comparing three follicular stages; 2) to identify cGMP targets by studying the phosphoproteome; and 3) to demonstrate the physiological involvement of cGMP in mediating ovarian functions using chemical agonists and inhibitors. This research program represents a major contribution to the current knowledge about improving oocyte quality during in-vitro maturation. This will impact the development of new reproductive biotechnology related to the quality of the female gamete, as well as lead to genetic improvements sought after by the pork industry. Finally, this research program assesses fundamental signaling which also has beneficial applications to other species such as dairy cattle.