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Exposure to tobacco smoke during pregnancy is a major contributor to perinatal morbidity and mortality. A major factor responsible for the deleterious effects of tobacco smoke on the developing fetus and neonate is thought to be nicotine. Nicotine produces acute cholinergic effects on the fetus and newborn by stimulating the nicotinic receptors (nAChR) on specific target cells in the nervous system. Nicotine has been shown to increase fetal plasma catecholamines and corticosterone. It also has been reported to interfere with maternal glucocorticoid and thyroxine regulation and act to cause fetal hypoglycemia. Transplacental exposure to nicotine may also have significant and widespread adverse effects on growth, development and behavior. The consequences of chronic administration of nicotine in early life are not known. Our overall goal is to understand the effects of nicotine and other drugs of abuse on the developing nervous system. The proposed studies will concentrate on one major nAChR subtype, alpha-7 (a7). The a7 receptor is expressed in both the central and peripheral nervous systems. The a7 gene contains a 5′ untranslated region (UTR) and alternative promoters that give rise to 5 different mRNA isoforms. The a7 promoter isoforms contain two TATA boxes, one of which contains an “enhancer” or “repressor” site that is located within a region of DNA that encodes a single exon common to all five mRNAs. Promoter elements and the DNA sequences between the promoters and the 5′ UTR interact with other transcriptional regulatory molecules and thereby regulate the level of expression of this gene. We have cloned the a7 gene promoter and have begun experiments to elucidate the role of the promoter elements in determining the developmental and tissue specific expression of this gene. The specific aims of the proposed studies are: 1) to understand the role of the a7 gene promoter and splicing factor in regulating tissue specific expression and the developmental regulation of the gene in the nervous system; 2) to identify factors responsible for the tissue specific expression of the gene in the liver. The successful completion of these studies will increase our understanding of the role of a7 gene expression in the developing nervous system and provide data to support the hypothesis that nAChRs are involved in neuromodulation at all stages of CNS development.New York (CNN Business) The App Store is stocked with endless fun games that you can play on your iPhone, and the games play just as well on

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