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: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684580
• 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。单元格作为单个实体或组的一部分发挥作用。细胞对其环境的适当反应是非常重要的，不仅对细胞的生存，而且对发挥生理作用。细胞对荷尔蒙刺激的反应涉及信号转导，其中往往包括环核苷酸作为关键角色。近几十年来，环磷酸腺苷(CAMP)比环鸟苷(CGMP)研究得更多。在卵巢中，cAMP在卵泡刺激素(FSH)和黄体生成素(LH)中的作用已被表征，并在类固醇合成中被研究，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的作用受到越来越多的关注。这一模型表明，cGMP主要由颗粒细胞和卵丘细胞对C型利钠肽的反应而合成。CGMP通过缝隙连接在颗粒细胞、卵丘细胞和卵母细胞之间形成电生理合胞，使cGMP从颗粒细胞扩散到卵母细胞，从而抑制卵母细胞的磷酸二酯酶。这种酶抑制增加了卵母细胞内cAMP，从而阻止了减数分裂的恢复。然而，对cGMP在卵泡中的作用知之甚少。CGMP不太可能只是等待转移到卵母细胞。CGMP的目标是什么？CGMP有哪些生理影响？CGMP是否调节cAMP反应？*拟议研究计划的长期目标是加深我们对信号转导在卵泡不同生理反应中的重要性的理解。由于cAMP介导促卵泡激素和促黄体生成素的反应，如细胞分化，假设cGMP作为第二信使发挥重要的生理作用，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描述cGMP信号转导的分子机制；2)通过研究磷酸蛋白质组来确定cGMP靶点；3)证明cGMP在使用化学激动剂和抑制剂调节卵巢功能中的生理作用。*这项研究计划代表了对目前关于在体外成熟过程中改善卵母细胞质量的认识的重大贡献。这将影响与雌配子质量相关的新生殖生物技术的发展，并导致猪肉行业寻求的基因改良。最后，这项研究计划评估了基本信号转导，这对其他物种也有有益的应用，如奶牛。