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15％夫妻。在这些夫妇中，约40％的夫妇患有排卵功能障碍。排卵是Folliculo-的顶峰 - 创世纪，这是一个需要颗粒细胞（GC）增殖和分化的过程叶状形成。稳定的植物生长在排卵前的阶段和预防卵泡闭锁的依赖在刺激叶子的马内（FSH）上。 FSH是用于刺激OVU-患者叶片生长的主要药物功能障碍。但是，每日剂量和最佳叶片生长变化所需的FSH总量受控卵巢过度刺激的患者之间相当大多。这种不确定性很大 CERN作为高剂量FSH的影响，即使没有有害，也是可疑的。卵巢反应差的患者（POR）至卵巢刺激特别容易受到此问题的影响。目前，虽然很明显改善POR患者反应的常见临床方法是使用更高剂量的FSH，这种方法没有明显的优势。这表明迫切需要确定是否存在固有的抑制作用 - 保守因素减少了FSH行动。阻止对卵泡发生负面影响的因素的影响改善叶片的生长和生育能力。初步结果表明盐诱导激酶（SIKS）为负卵泡发生，雌二醇产生和GC分化的调节剂。此外，提示的初步数据 Siks调节CRTC2是CREB的辅助因子，STK11和GSK3β等激酶是上游的锡克斯。我们假设Siks构成了阻碍机制的一部分，以防止GC apop- 促进GC分化，并保证卵泡发生的正常进展。测试这个假设 SIS，我们将追求以下目标。 1：确定卵巢植物生长和雌性受精的SIK功能 - IHC数据显示了GC，SIK2和/或SIK3 GC条件中SIK2和SIK3的高表达敲低小鼠将用于揭示女性生育力中锡克的功能。 2：定义Sik下游焦油 - 进入人类和鼠标GC。这个目标旨在增进我们对物理机械的理解由GCS中的Siks控制的NISM。 3：确定GCS中SIKS的上游调节剂。我们假设在没有FSH的情况下，STK11和GSK3β的组合作用都高度活跃，维持BA- SIKS在GC中的SAL抑制活性以及GSK3β活性的FSH抑制作用对于终止阻塞至关重要 SIKS对GC分化和生存的影响。在该项目结束时，我们预计将解锁密钥卵巢中的Sik家族精心策划的植物事件。因为SIK活动可以是在身体上进行调制，更好地理解锡克的控制机制和途径可能有助于生育能力的新型热发展的发展，使排卵更安全，更有效地诱导在妇女中。 SIK管制的机制可能揭示了创新逆向发展的新目标征收方法。