Examining the importance of ADAM metalloproteinases in trophoblast biology

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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 embryo ‘invade’ into the wall of the uterus, attaching the embryo. These cells, called the trophoblast, then divide to create multi-nuclear structures that enable transfer of oxygen and nutrients between mother and 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. My research program in placental biology focuses on trophoblast biology, with the long-term objectives of understanding (1) the role of unique trophoblast cell populations in placental development, including the factors affecting trophoblast behavior; and (2) the cellular and molecular mechanisms involved in trophoblast maturation and function. The research proposed here is the first step towards these objectives. In the short-term, my aim is to characterize the significance of the molecule ADAM12, and related members of the A Disintegrin and Metalloproteinase (ADAM) gene family in trophoblast cell biology. ADAM genes have unique characteristics that enable them to affect processes common in many developmental pathways. In particular, these molecules are involved in cell adhesion and movement. The proposed studies will test the hypothesis that ADAM proteins play a central role in trophoblast function and placenta development. Using cultured trophoblast cells and tissues derived from harvested placenta, I will use advanced cellular and molecular methods to determine how ADAM’s affect trophoblast cell behavior and function. These studies will improve our understanding of the molecular mechanisms involved in trophoblast biology and placental formation. This work will also contribute new knowledge about ADAM proteins, with respect to its importance in developmental biology and in other organ systems.