Defining the role of ACKR3 in implantation success

Successful embryo implantation in the maternal endometrium is vital for pregnancy establishment. Despite impressive advancements in assisted fertilization, high rates of implantation failure remain a leading cause of infertility for couples. A primary criterion for establishing endometrial receptivity is the formation of pinopodes on the surface of the uterus. We have previously shown that adrenomedullin (AM=protein, Adm=gene) is a major driver of pinopode formation in mice, as genetic decrease in Adm leads to reduced pinopodes while therapeutic delivery of AM increases pinopode size and number. Notably, reduction of fetal-expressed levels of Adm causes an increase in the occurrence and severity of implantation defects, but can be reversed by increasing AM fetal levels. Thus, identifying factors that can control AM dosage during implantation may lead to novel therapies for improved fertility. Recently, we discovered that atypical chemokine receptor 3 (ACKR3) can tightly control AM protein levels and function in the heart. Yet, the precise mechanism coordinating ACKR3-AM signaling during early pregnancy remains elusive. Thus, my primary objective is to elucidate whether and how ACKR3 regulates AM signaling and function during implantation using cutting-edge in vitro and in vivo genetic models. This research will contribute significantly to the Lalor Foundation mission by identifying a novel cohort of therapeutic targets for the amelioration of fertility success in women.