Salt-Inducible Kinase Regulation of Ovarian Granulosa Cells

不孕不育是国家卫生研究所确定的主要公共卫生问题之一，影响到15%的人 一对情侣。在这些夫妇中，约有40%的女性有排卵障碍。排卵是卵泡的顶峰-- 发生，排卵前都需要颗粒细胞(GC)的增殖和分化 毛囊形成。卵泡向排卵前期的稳定生长和卵泡闭锁的预防依赖于 关于卵泡刺激素(FSH)。卵泡刺激素(FSH)是目前用于促进卵巢癌患者卵泡生长的主要药物。 呼吸功能障碍。然而，最佳卵泡生长所需的每日剂量和FSH总量各不相同。 在接受控制性卵巢过度刺激的患者之间有相当大的差异。这种不确定性具有极大的欺骗性-- CERN作为高剂量FSH的影响是值得怀疑的，如果不是有害的话。卵巢反应差的患者 卵巢刺激(POR)尤其易受此问题的影响。目前，虽然最明显和最 改善POR患者反应的常见临床方法是使用更大剂量的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内在的抑制作用。 减少促卵泡激素作用的保守因素。阻断负面影响卵泡发生的因素的影响可能 提高卵泡生长和生育力。初步结果表明，盐诱导的蛋白激酶(Sik)是阴性的。 卵泡发生、雌二醇产生和GC分化的调节剂。此外，初步数据显示 SIKS调控CREB辅因子CRTC2，而STK11和GSK3等β等激酶位于CREB的上游 希克斯。我们假设SIKS是阻碍机制的一部分，必须阻止这种机制以防止GC APOP- 促进GC分化，保证卵泡发育的正常进行。为了检验这个假说- SIS，我们将追求以下目标。1：测定SIK在卵泡生长和女性受精中的作用 城市。基于IHC数据显示SIK2和SIK3在GC、SIK2和/或SIK3条件GC中高表达 基因敲除的小鼠将被用来揭示SIKS在女性生育中的作用。2：定义SIK下游焦油- 感染了人类和小鼠的GC。这一目的旨在增加我们对生理机制的理解-- 在GC中由SIKS控制的NIMS。3：确定大中华区SIKS的上游监管机构。我们假设 在没有卵泡刺激素的情况下，STK11和GSK3β的结合作用都非常活跃，维持了BA值。 SIKs在GCs中的β抑制活性以及FSH抑制Gsk3的SAL活性是终止阻断的关键 SIKS对GC分化和存活的影响。在这个项目结束时，我们预计将有解锁的密钥模块- 由卵巢中的SIK蛋白家族精心策划的特定事件。由于SIK活动可以 在药理学上，更好地理解SIK控制的机制和途径可能有助于 允许更安全、更有效地诱导排卵的生育治疗新进展 在战俘女性身上。SIK调控机制可能为创新逆转录病毒的发展提供新的靶点 概念方法。

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.