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 GSK3? 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 GSK3?, 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 GSK3? 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.
This project is relevant to public health because a full understanding of the mechanisms involved in the for- mation of preovulatory follicles will provide the foundation for perfecting the diagnosis and treatment of ovulatory defects and for improving IVF outcomes. This project will generate knowledge that will help reduce the burden of infertility treatments.
