Effects of leptin and its Mechanisms of Action on Mammalian Trophoblast Cells

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Central to an understanding of successful pregnancies is determining how the placentaattaches itself to the uterine wall of the mother. The outer lining of the placenta contains a layerof cells (trophoblasts), which have the property of being able to invade the uterine lining, thusestablishing the placenta. How the invasion process is initiated and regulated is uncertain. Inthis project, the hypothesis that the reproductive hormone leptin stimulates invasiveness oftrophoblast cells will be investigated in trophoblast cells grown on an artificial, protein-coatedmembrane. Invasive cells secrete enzymes that degrade the protein coating, and permit the cellsto move through tiny pores in the membrane; the number of cells penetrating the membrane arecounted under a microscope. The ability of leptin to stimulate invasion of trophoblasts fromplacentas at early and late gestation will be examined; we predict that leptin will promoteinvasion only in trophoblasts from early-stage placentas. The molecular mechanisms by whichleptin stimulates invasiveness will be determined by examining changes in intracellular signalingmolecules and gene expression induced by leptin. Placentas will be studied in speciesrepresenting the two most abundant mammalian orders. The mouse placenta does not produceleptin, but expresses receptors for leptin and is therefore sensitive to leptin actions. The littlebrown bat placenta produces and secretes leptin (as does the human placenta), and like the mouseplacenta is a target for leptin. The effects of leptin on mouse and bat placental function will becompared. Broader impacts of this project include: 1) documentation of the importance of leptinin establishing the placenta in diverse mammals; 2) understanding the role of leptin as a generalsignal for cell migration and invasion (i.e., in other cell types where leptin is known to act andwhere cells are invasive); 3) understanding gestational stage-dependent actions of hormones ontrophoblast cells; and 4) education of young scientists-in-training and outreach to includeparticipation of underrepresented minorities (one postdoctoral fellow, one to two graduatestudents and four undergraduates students will be mentored per year on this project).