Cell signaling in ovarian function

卵巢功能中的细胞信号传导

• 批准号: RGPIN-2019-04496
• 负责人: Richard, François
• 金额: $ 2.4万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713464
• 关键词: Cell; signaling; ovarian; function

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.

细胞是生命的单位。一个单元作为一个单独的实体或作为一个组的一部分。细胞对其环境的适当反应非常重要，不仅对于细胞的存活，而且对于执行生理作用。细胞对激素刺激的反应涉及信号转导，其中通常包括环核苷酸作为关键参与者。近几十年来，环磷酸腺苷（cAMP）的研究比环磷酸鸟苷（cGMP）多得多。在卵巢中，cAMP的贡献已被表征为对促卵泡激素（FSH）、促黄体生成激素（LH）的响应，并在类固醇生成中进行了研究，但cGMP在卵泡细胞中的作用如何？在过去的几年里，cGMP的贡献得到了更多的关注，因为在哺乳动物卵母细胞减数分裂恢复的抑制模型。该模型表明cGMP主要由颗粒细胞和卵丘细胞响应于C型利钠肽而合成。通过间隙连接在颗粒细胞、卵丘细胞和卵母细胞之间产生的电生理合胞体允许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。这种酶抑制增加卵母细胞内cAMP，阻断减数分裂恢复。然而，对cGMP在卵泡中的作用知之甚少。cGMP不太可能只是等待移动到卵母细胞。cGMP的目标是什么？cGMP的生理影响是什么？cGMP调节cAMP反应吗？ 拟议的研究计划的长期目标是完善我们的理解，在不同的生理反应的卵泡信号转导的重要性。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，它在卵泡细胞中的生理作用是什么？短期目标是：1）通过比较三个卵泡阶段来表征参与cGMP信号传导的分子机制; 2）通过研究磷酸化蛋白质组来识别cGMP靶点; 3）使用化学激动剂和抑制剂来证明cGMP在介导卵巢功能中的生理参与。 这项研究计划是对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相关的新生殖生物技术的发展，并导致猪肉行业所追求的遗传改良。最后，这项研究计划评估了基本信号，这也有有益的应用到其他物种，如奶牛。