Salt-Inducible Kinase Regulation of Ovarian Granulosa Cells

卵巢颗粒细胞的盐诱导激酶调节

基本信息

批准号：
10643707
负责人：
CARLOS OSCAR STOCCO
金额：
$ 33.23万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-06 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10643707
关键词：
Affect Agriculture Apoptosis Aromatase CREB1 gene Cell Differentiation process Cell Proliferation Cell Survival Cell physiology Clinical Contraceptive methods Couples Cyclic AMP Data Defect Development Diagnosis Dose Drug usage Estradiol Event Family Fertility Fertility Disorders Follicle Stimulating Hormone Follicular Atresia Foundations Gatekeeping Graafian Follicles Growth Human Infertility Knockout Mice Knowledge Livestock Mediating Methods Molecular Mus Oocytes Outcome Ovarian Ovarian Follicle Ovarian Granulosa Cell Ovarian Hyperstimulation Syndrome Ovarian Stimulations Ovary Ovulation Ovulation Induction Pathway interactions Patients Pharmaceutical Preparations Phosphorylation Phosphotransferases Physiological Predisposition Prevention Process Production Productivity Public Health Publishing Regulation Repression Role STK11 gene Testing Uncertainty United States National Institutes of Health Woman advanced maternal age cofactor female fertility folliculogenesis glycogen synthase kinase 3 beta granulosa cell hormonal signals improved in vivo infertility treatment innovation kinase inhibitor knock-down negative affect novel therapeutics ovarian dysfunction ovarian reserve patient response pharmacologic prevent response salt-inducible kinase subfertility translational study upstream kinase

项目摘要

Infertility is one of the major public health problems identified by the National Institute of Health that affects 15% of couples. In ~40% of these couples, the woman has ovulatory dysfunction. Ovulation is the pinnacle of folliculo- genesis, a process that requires granulosa cell (GC) proliferation and differentiation both needed for preovulatory follicle formation. Steady follicle growth towards the preovulatory stage and prevention of follicular atresia depend on follicle-stimulating hormone (FSH). FSH is the main drug used to stimulate follicle growth in patients with ovu- latory dysfunction. However, the daily doses and the total amount of FSH needed for optimal follicle growth vary considerably between patients undergoing controlled ovarian hyperstimulation. This uncertainty is of great con- cern as the effects of high doses of FSH are questionable if not harmful. Patients with a poor ovarian response (POR) to ovarian stimulation are particularly susceptible to this problem. Currently, while the obvious and most common clinical approach to improve the response of POR patients is to use higher doses of FSH, this approach does not have a clear advantage. This points to the urgent need to determine whether there are intrinsic inhibi- tory factors that diminish FSH actions. Blocking the effects of factors that negatively affect folliculogenesis could improve follicle growth and fertility. Preliminary results suggest that salt-inducible kinases (SIKs) are negative regulators of folliculogenesis, estradiol production, and GC differentiation. In addition, preliminary data indicate that SIKs regulate CRTC2, a cofactor of CREB, and that kinases such as STK11 and GSK3β are upstream of SIKs. We hypothesize that SIKs form part of a hampering mechanism that must be inhibited to prevent GC apop- tosis, to aid GC differentiation, and to guarantee the normal progression of folliculogenesis. To test this hypothe- sis, we will pursue the following aims. 1: Determine SIK function in ovarian follicle growth and female fertil- ity. Based on IHC data showing high expression of SIK2 and SIK3 in GCs, SIK2 and/or SIK3 GC-conditional knockdown mice will be used to uncover the function of SIKs in female fertility. 2: Define SIK downstream tar- gets in human and mouse GCs. This aim seeks to increase our understanding of the physiological mecha- nisms controlled by SIKs in GCs. 3: Identify the upstream regulators of SIKs in GCs. We hypothesize that the combinatory actions of STK11 and GSK3β, which are both highly active in the absence of FSH, maintain the ba- sal inhibitory activity of SIKs in GCs and that FSH inhibition of GSK3β activity is crucial to terminate the blocking effects of SIKs on GC differentiation and survival. At the end of this project, we expect to have unlocked key mo- lecular events that are orchestrated by the SIK family of kinases in the ovary. Since SIK activity can be modulated pharmacologically, a better understanding of SIK-controlled mechanisms and pathways may facilitate the development of novel therapeutic advances in fertility allowing safer and more effective induction of ovulation in POR women. SIK regulated mechanisms could reveal new targets for the development of innovative contra- ception methods.

不孕不育是美国国立卫生研究院确定的主要公共卫生问题之一，影响着 15% 的人其中约 40% 的夫妇存在排卵功能障碍。发生，一个需要颗粒细胞 (GC) 增殖和分化的过程，两者都是排卵前所需的卵泡的形成取决于排卵前阶段的卵泡稳定生长和卵泡闭锁的预防。促卵泡激素（FSH）是用于刺激卵泡患者卵泡生长的主要药物。然而，最佳卵泡生长所需的每日剂量和 FSH 总量各不相同。这种不确定性在接受受控卵巢过度刺激的患者之间存在很大差异。对于卵巢反应较差的患者，高剂量 FSH 的影响即使没有危害，也是值得怀疑的。（POR）卵巢刺激特别容易出现这个问题，而目前最明显。改善POR患者反应的常见临床方法是使用更高剂量的FSH，这种方法不具有明显的优势，这一点迫切需要确定是否存在内在的抑制剂。阻止对卵泡发生产生负面影响的因素的影响。改善卵泡生长和生育能力初步结果表明盐诱导激酶 (SIK) 呈阴性。此外，初步数据表明，卵泡发生、雌二醇产生和 GC 分化的调节因子。 SIK 调节 CRTC2（CREB 的辅助因子），并且 STK11 和 GSK3β 等激酶是 CRTC2 的上游 SIK 是阻碍机制的一部分，必须加以抑制才能防止 GC 凋亡。来帮助 GC 分化，并保证卵泡发生的正常进展。 sis，我们将追求以下目标 1：确定 SIK 在卵泡生长和女性生育能力中的功能。基于显示 GC 中 SIK2 和 SIK3 高表达的 IHC 数据，SIK2 和/或 SIK3 GC 条件。敲除小鼠将用于揭示 SIK 在女性生育力中的功能 2：定义 SIK 下游目标。该目标旨在增加我们对人类和小鼠 GC 的生理机制的理解。 GC 中 SIK 控制的机制 3：确定 GC 中 SIK 的上游调节因子。 STK11 和 GSK3β 的组合作用在缺乏 FSH 的情况下都高度活跃，可维持 ba- GC 中 SIK 的 sal 抑制活性，并且 FSH 抑制 GSK3β 活性对于终止阻断至关重要 SIK 对 GC 分化和存活的影响在本项目结束时，我们期望能够解开关键的机制。 SIK 激酶家族在卵巢中精心策划的分子事件。通过药理学调节，更好地了解 SIK 控制机制和途径可能有助于生育方面新的治疗方法的发展使得诱导排卵更安全、更有效在 POR 女性中，SIK 监管机制可以揭示创新对抗发展的新目标。接待方式。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Salt-inducible Kinases Are Critical Determinants of Female Fertility.

盐诱导激酶是女性生育能力的关键决定因素。

DOI：
发表时间：
2020
期刊：
影响因子：
4.8
作者：
Armouti, Marah;Winston, Nicola;Hatano, Osamu;Hobeika, Elie;Hirshfeld;Liebermann, Juergen;Takemori, Hiroshi;Stocco, Carlos
通讯作者：
Stocco, Carlos

Oocyte-secreted factors strongly stimulate sFRP4 expression in human cumulus cells.

卵母细胞分泌因子强烈刺激人卵丘细胞中 sFRP4 的表达。

DOI：
发表时间：
2021
期刊：
影响因子：
4
作者：
Esfandyari, Sahar;Winston, Nicola J;Fierro, Michelle A;Scoccia, Humberto;Stocco, Carlos
通讯作者：
Stocco, Carlos

Insulin-like growth factor 1 enhances follicle-stimulating hormone-induced phosphorylation of GATA4 in rat granulosa cells.

胰岛素样生长因子 1 增强大鼠颗粒细胞中促卵泡激素诱导的 GATA4 磷酸化。

DOI：
发表时间：
2023-01-01
期刊：
影响因子：
4.1
作者：
Convissar, Scott;Bennett;Stocco, Carlos
通讯作者：
Stocco, Carlos

Salt-inducible kinases regulate androgen synthesis in theca cells by enhancing CREB signaling.

盐诱导激酶通过增强 CREB 信号传导来调节卵泡膜细胞中的雄激素合成。

DOI：
发表时间：
2023-11-01
期刊：
影响因子：
4.1
作者：
Rodriguez Esquivel, Miriam;Hayes, Emily;Lakomy, Oliwia;Hassan, Mariam;Foretz, Marc;Stocco, Carlos
通讯作者：
Stocco, Carlos

Mechanism of negative modulation of FSH signaling by salt-inducible kinases in rat granulosa cells.

大鼠颗粒细胞中盐诱导激酶负调节 FSH 信号传导的机制。