Salt-Inducible Kinase Regulation of Ovarian Granulosa Cells

不孕症是国家卫生研究所确定的主要公共卫生问题之一， 情侣。在这些夫妇中，约40%的女性患有排卵功能障碍。排卵是卵泡发育的顶峰- 生殖，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。 卵泡形成卵泡向排卵前阶段的稳定生长和卵泡闭锁的预防依赖于 促卵泡激素（FSH）。FSH是用于刺激排卵患者卵泡生长的主要药物， 排尿功能障碍然而，卵泡生长最佳所需的每日剂量和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显著差异。这种不确定性具有很大的不确定性。 因为高剂量FSH的作用即使不是有害的，也是值得怀疑的。卵巢反应不良的患者 (POR)对卵巢刺激特别敏感。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高剂量的FSH，这种方法 并没有明显的优势。这表明迫切需要确定是否存在内在的免疫缺陷- 减少FSH作用的保守因素。阻断对卵泡生成产生负面影响的因素的影响， 促进卵泡生长和生育能力。初步结果表明，盐诱导激酶（SIKs）是阴性的， 卵泡发生、雌二醇产生和GC分化的调节因子。此外，初步数据显示， SIKs调节CREB的辅因子CRTC 2，而激酶如STK 11和GSK 3 β位于CRTC 2的上游， SIKs。我们假设SIKs形成了一种阻碍机制的一部分，必须抑制这种机制以防止GC apop。 促进GC分化，保证卵泡发育的正常进行。为了测试这个假设- 妹妹，我们会致力达致以下目标。1：确定卵巢卵泡生长和女性生育中的SIK功能- ity。基于显示SIK 2和SIK 3在GC中的高表达的IHC数据，SIK 2和/或SIK 3 GC条件性 敲除小鼠将用于揭示SIKs在女性生育力中的功能。2：定义SIK下游焦油- 在人和小鼠的GC中。这一目标旨在增加我们对生理机制的理解- 在GC中由SIK控制的nisms。3：确定GC中SIK的上游调节因子。我们假设 STK 11和GSK 3 β的联合作用，在没有FSH的情况下都是高度活跃的，维持了基础。 GCs中SIKs抑制活性和FSH对GSK 3 β活性的抑制是终止阻断的关键 SIKs对GC分化和存活的影响。在这个项目结束时，我们希望有解锁的关键莫- 由卵巢中的激酶的SIK家族精心安排的细胞事件。由于SIK活动可以 调制的，更好地了解SIK控制的机制和途径可能有助于 开发新的生育治疗进展，允许更安全和更有效的诱导排卵 在POR女性中。SIK调节机制可以揭示创新对抗疾病发展的新目标， 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.