Grant: Discovery Grants Program - Individual

BACKGROUND: Correct formation of the placenta is one of the most important determinants of successful reproduction in mammals. The placenta forms the mechanical and physiologic link between mother and fetus, supporting growth and development. If it does not develop properly, there can be serious problems, including death, for both mother and offspring. The placenta develops after a special group of cells that are part of the blastocyst `invade' into the wall of the uterus, attaching the embryo. These cells, called trophoblasts, then expand to create cellular structures that enable transfer of oxygen and nutrients between mother and fetus, and further instruct a local environment of tolerance towards the developing fetus. Despite the importance of the placenta, we still have a poor understanding of the cellular and molecular events involved in the critical early stages of its formation. RECENT PROGRESS: Over the past five years, my lab has examined if ADAM proteases and exposure to low oxygen control invasive trophoblast functions. Using 3D placental explant systems that recapitulate many of the cellular events occurring during placental development and state-of-the-art single cell sequencing, we show that specific ADAMs promote trophoblast invasion and low oxygen accelerates trophoblast differentiation into invasive subtypes. OBJECTIVES: Building on my laboratory's long-term objective to identify and characterize novel molecular and cellular processes important in trophoblast biology and placental development, I will advance this via two short-term objectives: 1) testing if ADAM proteases control EVT differentiation; and 2) identifying hypoxia-regulated pathways controlling EVT differentiation. METHODOLOGY: The proposed studies will test the hypothesis that ADAM proteases and low O2 tension promote trophoblast differentiation along the invasive extravillous pathway. Using trophoblast organoid cultures and 3D placental explant systems, I will incorporate state-of-the-art single cell sequencing and gene-editing methods to determine if ADAM proteases coordinate trophoblast differentiation and identify how hypoxia drives invasive trophoblast specification. HQP: I intend to train a diverse group of 8 HQP over the timeline of this support. In the training of these HQP, I will implement equitable and inclusive recruitment and mentoring practices. IMPACT: These studies will improve our understanding of the molecular mechanisms involved in trophoblast biology and placental formation, of which there is currently little knowledge. This work will also generate new knowledge about ADAM proteases and oxygen-sensing systems that are likely conserved in other cellular systems and organs, and may therefore indirectly contribute to fields of stem cell and developmental biology.