This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. According to the latest statistics from the CDC, in 1999, 12.3% of American women smoked during pregnancy, translating to over 400,000 smoke-exposed infants. Smoking during pregnancy is the largest preventable cause of low birth weight, premature delivery, neonatal morbidity and mortality. Further, it has been estimated that 10% of all fetal and neonatal deaths are due to smoking during pregnancy. Smoking during pregnancy directly and adversely affects lung development as manifested by altered pulmonary function and increased respiratory illness in children born of smoking mothers. Remarkably, how smoking produces these effects is unknown. While the cause of pulmonary damage caused by maternal smoking is likely to be multifactorial, it is the hypothesis of this project, based on discoveries we previously made in rhesus monkeys, that part of the effect of maternal smoking on lung is mediated by nicotine transported across the placenta to interact with alpha7 nicotinic receptors in developing lung. In this project, alpha7 knockout and alpha7 gain of function mice, will be used to study the link between the effects of prenatal nicotine exposure and alpha7 nAChR. Based on our preliminary data and epidemiologic data on human infants, we will focus on 3 aspects of smoking's effects on lung development: pulmonary function as measured by active and passive tests, cell growth, and collagen expression. From these studies will come some of the first explanations of the molecular mechanisms that underlie the effects of smoking during pregnancy on lung development. Understanding these mechanisms may lead to therapies to block the effects of smoking during pregnancy
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