Title of project

RANKL may be a novel and modifiable regulator of folliculogenesis: Insight from functional mouse, monkey, and human models.

Abstract

In recent years, female infertility has presented significant challenges for reproductive health globally. The underlying causes are multifactorial and despite intensive research efforts to uncover modifiable regulatory factors of ovarian development and folliculogenesis, such novel factors with clinical potential remain to be identified. Thus, there is an urgent need for effective interventions to address the premature or age-related decline in female fertility and provide treatment options for the affected women. Recent data indicates that some bone factors may affect fertility. One of the new players include the RANKL signalling system, which consists of the receptor activator of nuclear factor κΒ ligand (RANKL), the receptor RANK, and the decoy receptor osteoprotegerin (OPG). We have previously identified the RANKL system in the testis and found it to be a novel regulator of germ cell proliferation and maturation. However, the role of the RANKL system in female reproductive system remains unexplored.
Our preliminary data demonstrate that all components of the RANKL system are expressed in human and mouse ovarian follicles and that a substantial reduction in the number of primordial follicles is observed in a granulosa cell specific Rankl knock down mouse model. Hence, the present project is focusing on three primary objectives. The first objective is to study the reproductive effects of RANKL signalling using a global Rankl knock out mouse model and a granulosa cell specific Rankl knock down mouse model. The reproductive phenotypes as well as molecular effects will be assessed. The second objective focuses on nderstanding the early ovarian and follicular effects of RANKL signalling during development. For this, a human foetal ex vivo culture system will be employed to manipulate RANKL signalling. Effects of RANKL manipulation on proliferation, apoptosis, cell composition, as well as secreted factors will be evaluated. Finally, the effects of RANKL manipulation on ovarian function and reproductive hormones will be examined in higher primates. Thus, this project will provide important basic and translational knowledge on the RANKL system in ovarian development and folliculogenesis as well as on the effects of manipulating RANKL activity to determine whether this system may be a modifiable regulator of ovarian function.