Oxidant Stress and Allergic Asthma

描述(由申请人提供)： 氧化应激伴随着哮喘呼吸道的过敏性炎症。我们的中心假设是，哮喘炎症在一定程度上是由这种氧化应激介导的，氧化应激反过来又受到抗氧化酶基因决定的表达和饮食抗氧化剂的调节。谷胱甘肽S转移酶基因的多态可预测呼吸道高反应性、哮喘和特应性。GSTP1是一种在呼吸道上皮细胞中表达的多功能酶，它能解毒氧化应激产生的多种脂质和DNA产物，并具有不依赖于硒的过氧化物酶活性。为了验证我们的假设，我们建议在具有遗传特征的人类特应性哮喘患者中进行一系列实验，使用已建立的由局部或吸入变应原激发引起的过敏性呼吸道炎症模型。在整个实验中，将使用异前列腺素的测量来监测体内的氧化应激。异前列烷是脂质过氧化产生的自由基产物。在第一个具体目标中，我们将确定GSTP1的遗传变异是否对呼吸道中变应原引起的氧化应激进行不同的调节。在第二个具体目标中，我们将确定抑制呼吸道氧化应激所需的维生素E治疗剂量和时间。根据这一重要信息，我们将确定补充维生素E是否调节过敏性哮喘患者的非特异性气道高反应性和过敏原诱导的支气管痉挛。连接这两个特定目的的问题将是维生素E是否在具有不同GSTP1基因变异的个体中发挥不同的作用。这些研究应该提供关于过敏性哮喘中氧化应激和抗氧化防御的关键成分之间复杂相互作用的重要信息。了解抗氧化剂维生素在哮喘炎症中的作用对于正确使用抗氧化剂对哮喘患者是至关重要的。这项研究将促进未来以抗氧化剂为重点的新预防和治疗方法的研究。候选人提出的职业发展计划包括分子和临床遗传学、生物统计学、研究设计和分析的高级方法以及通过实验室和临床培训、课程工作和独立阅读进行研究项目管理的高级培训。除了他的出版记录和成就之外，他还将拥有丰富的学术环境、优秀的导师和强大的机构承诺，以确保他实现自己的目标。(摘要结束)

DESCRIPTION (provided by applicant): 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)