Clinical investigations provide insights into the environment and genetic regulation of pregnancy in humans. Furthermore, the wealth of discoveries on non-primates, especially mice, provide solid mechanistic hypothesis that can now be tested using genetic and epigenetic manipulations. This subproject bridges the gap between clinical research and the mouse studies by exclusively focusing on pregnancy in nonhuman primates. In addition to molecular and cell biological investigations, through the use of dynamic and non-invasive MRI and microPET with primates, including ones carrying transgenic reporters, we propose four specific aims. By building on the intellectual foundation of Project I, the first aim studying androgenotes and gynogenotes, answers problems regarding epigenetics and specifically genomic imprinting in primates. The second aim focuses on genetically unmanipulated animals. We will address two important goals. First, we will obtain longitudinal data throughout the gestation of "control" animals in order to better understand the progression of macrophage activation in the "normal" primate pregnancy and labor. Secondly, we will attempt to demonstrate a functional change in normal, full-term parturition as a result of blocking macrophage activation with IL- 10, a powerful anti-inflammatory cytokine. Building on the ability to generate and image successful "normal" pregnancies in Aim II, we will move to Aim III. The third aim addresses pregnancy outcome issues with regards to defined fetal and/or maternal genetics, including identical twins gestated sequentially in the identical surrogate versus identicals gestating simultaneously in different surrogates. These studies on the pregnancy establishment and fetal development segue to Aim IV, which examines the inflammatory responses to infectious threats to pregnancy and translates best obstetrical and perinatal clinical care to primate research resource management. The fourth aim investigates the consequences of one of the most important environmental threats to healthy pregnancies - intrauterine bacterial infection. In this aim, we will dynamically image in vivo the maternal and fetal inflammatory response to infection, and also attempt to attenuate that inflammatory response. This aim develops the pregnant primate system and tests the consequences of infection while Project III determines the genetic and epigenetic consequences of smoking during pregnancy in women and in mice.