Endocrine Abstracts

G-protein coupled receptors (GPCRs) represent the largest family of signaling receptors in nature. Their diversity means they play key physiological roles and their dysfunction underlies many pathological conditions, thus they are the focus of many drug design programs due to their primary biological and clinical importance. Our objective is to understand the fundamental mechanisms regulating hormone signaling via GPCRs. Disruption of GPCRs regulation in humans underlies many diseases including reproductive disorders and pregnancy complications, such as polycystic ovarian syndrome, ovarian cancer, infertility, recurrent miscarriage and pre-term births, so a crucial goal is to understand the consequences of these molecular processes on both normal physiological function and in disease. My project aims to elucidate the cellular machinery involved in LH and human chorionic gonadotrophin (hCG) re-ceptor (LH/CG-R) signal regulation and its potential implications in recurrent pregnancy loss. This GPCR is essential in maintaining normal human reproduction by regulating ovulation, spermatogenesis and maintenance of early pregnancy (via actions of the pregnancy hormone hCG). hCG and the LH/CG-R may also play additional roles during pregnancy including regula-tion of embryo implantation and immune responses of the mother, and it is known to be ex-pressed in human endometrial stromal cells (HESCs) which forms part of the lining of the uterus. Preliminary data in the laboratory has indicated that hCG-induced receptor signaling in HESCs is not coupled to the Gαs- pathway (which is the classical pathway of this receptor), but to the Gαi-pathway. Additionally, there may be a change in the constitutive activity of this recep-tor between differentiated and non-differentiated HESCs. To our knowledge, no other previous reports have shown a GPCR to change its constitutive activity in the same cell type and this is an exciting novel aspect that will be investigated further in this project. Thus, the overall aim of this project is to unravel the mechanisms underlying the unique signalling and regulatory properties of the LH/CG-R in human endometrium and how such mechanisms could be altered in women with recurrent pregnancy loss.

Declaration of funding: Genesis Research Trust.