? ? Oxidant stress accompanies allergic inflammation in the asthmatic airway. Our central hypothesis is that asthmatic inflammation is mediated in part by this oxidant stress which is in turn regulated by the genetically determined expression of antioxidant enzymes and by dietary antioxidants. Polymorphisms of the glutathione S transferase (GSTP1) gene predict airway hyperreactivity, asthma, and atopy. GSTP1 is a multifunctional enzyme expressed in airway epithelium which detoxifies a variety of lipid and DNA products of oxidative stress and possesses selenium-independent peroxidase activity. To test our hypothesis we propose performing a series of experiments in genetically characterized human atopic asthmatics using well established models of allergic airway inflammation provoked by local or inhaled allergen challenge. Measurement of isoprostanes, the free radical-generated products of lipid peroxidation, will be employed throughout the experiments to monitor oxidant stress in vivo. In the first specific aim, we will determine if the genetic variants of GSTP1 differentially regulate oxidant stress caused by allergen in the airways. In the second specific aim we will establish the dose and time of treatment with vitamin E necessary to suppress oxidative stress in the airways. With this important information we will determine if supplementation with vitamin E modulates nonspecific airway hyperresponsiveness and allergen induced bronchospasm in allergic asthma. The question connecting the two specific aims will be whether vitamin E exerts different roles in individuals with various genetic variants of the GSTP1.These studies should provide important information about complex interactions between oxidative stress, and the critical components of the antioxidant defenses in allergic asthma. Understanding of the role of antioxidant vitamins in asthmatic inflammation is essential for their appropriate utilization in asthmatics. The study will stimulate future research on new prophylactic and treatment methods focused on antioxidant agents. The candidate's proposed career development plan includes advanced training in molecular and clinical genetics, biostatistics, advanced methods of study design and analysis, and research project administration through laboratory and clinical training, course work, and independent reading. Along with his record of publications and achievement, he will have rich academic surroundings, excellent mentors, and strong institutional commitment to ensure that he accomplishes his goals. (End of Abstract) ? ? ? ? ? ? ?
