Grant: $278,729 - National Institutes of Health - Sep. 17, 2009
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Award Description: This competitive revision will stringently adhere to the ARRA by retaining the position of a Research Associate and creating one position for a Research Assistant and a part-time position for an undergraduate student and stimulating the economy through the purchase of genotyping services from a large US-based company. This revision also serves to create new research objectives to explore the associations of nicotine metabolism and oxidative stress genetics outside of the scope of the parent grant, and will be completed in less than one year. ETS exposure is a major contributor to childhood respiratory disorders. Nicotine and cotinine measures serve as a proxy for systemic exposure to over 4700 chemicals present in ETS, many with pro-inflammatory properties, including nicotine. ETS also induces the production of reactive oxygen species (ROS) and oxidative stress, which are deactivated primarily by enzymes in the glutathione-S-transferase (GST) family. Functional polymorphisms have been identified in genes related to nicotine metabolism and oxidative stress that can decrease cotinine formation (and therefore increased nicotine), and deactivation of ROS. The central hypothesis is that carriers of variant alleles in nicotine metabolism and/or oxidative stress related genes may have increased systemic nicotine, and therefore misclassification of ETS biomarkers, and increased prevalence and exacerbation of respiratory disorders, including asthma. We will test this hypothesis with the following aims: 1) Determine the effects of variant alleles in nicotine metabolism genes on biomarkers of nicotine and cotinine. We hypothesize that variant alleles in multiple genes along the nicotine metabolism pathway will cause increased systemic nicotine and decreased cotinine formation, leading to misclassification of ETS biomarkers. 2) Examine the associations of nicotine metabolism and oxidative stress related genes on respiratory outcomes. We hypothesize that children with variant alleles in nicotine metabolizing and/or oxidative stress related genes will have increased prevalence and exacerbation of respiratory disorders. This competitive revision will evaluate subjects participating CCAAPS, a well-characterized birth cohort at high-risk for development of allergic disease, whose main objective is to determine the effects of diesel exhaust on childhood allergic disease and asthma. Objective measures of respiratory disease, including asthma, as well as DNA, hair samples and parental report of ETS exposures are currently being collected from the children aged seven by the parent cohort. This revision proposes to genotype nicotine metabolism and oxidative stress related genes for both functional and tagging single nucleotide polymorphisms (SNPs), as well as quantify nicotine and cotinine in hair samples. The research proposed is significant because it will provide novel information on the need to consider genetic make-up when quantifying nicotine and cotinine as biomarkers of ETS exposure in epidemiologic studies. Further, this research may provide a basis for development of future therapies that identify children that are genetically susceptible to respiratory disorders.
Project Description: As defined in the Award Description field.
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Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 17, 2009. Help expand these official descriptions using the wiki below.