Project description

The endometrium is one of the body’s most dynamic and energy-demanding tissues, undergoing an incredible transformation in its 28-day lifespan. When menstruation starts, the endometrial tissue must undergo rapid repair in 2-3 days and regenerate to form a thickened layer capable of supporting an implanting embryo in ~9 days, followed by just six days to undergo further changes critical for embryo implantation. This rapid rejuvenation and transformation requires a high rate of cellular energy production. Ensuring that the endometrium can produce sufficient energy for tissue development and remodelling may improve uterine receptivity.

We recently published a seminal study demonstrating that creatine, a compound obtained from our diet and synthesised by the body, is an important energy substrate in the human endometrium. Our study found that the endometrium’s epithelial, stromal and glandular cells express the proteins required to produce and use creatine to generate energy. We discovered that this capacity is highest during the menstrual cycle when implantation occurs, and there are differences between women with primary infertility compared to controls in the capacity of these cells to produce and transport creatine. What remains to be determined is the specific role of creatine in supporting endometrial energy turnover and embryo implantation and whether uterine creatine concentrations are lower in women who experience miscarriage or pregnancy complications.

The global aim of this PhD project is to understand the importance of uterine creatine metabolism across the menstrual cycle and around the time of embryo implantation. To meet our objectives, this project will include three aims using pre-clinical animal models and clinical samples with next-generation laboratory techniques and analyses. Specifically:

Aim 1 | To characterise endometrial creatine metabolism at the point of embryo implantation using the spiny mouse, a rodent with unique reproductive biology, including spontaneous decidualisation and menstrual bleeding.

Aim 2 | Using spatial mass spectrometry, characterise creatine production and utilisation by human endometrial cells throughout the menstrual cycle in healthy participants and those experiencing primary infertility.

Aim 3 | To investigate changes in endometrial creatine metabolism associated with adverse pregnancy outcomes by conducting metabolomic and proteomic analyses in menstrual fluid samples (derived from the EOS Cohort Study).