Oxidant Stress and Allergic Asthma

描述（由申请人提供）： 氧化应激伴随哮喘气道过敏性炎症。我们的中心假设是，哮喘炎症部分介导的氧化应激，这反过来又调节基因决定的抗氧化酶的表达和饮食中的抗氧化剂。谷胱甘肽S转移酶（GSTP1）基因多态性可预测气道高反应性、哮喘和特应性GST P1是一种在气道上皮中表达的多功能酶，其对氧化应激的多种脂质和DNA产物进行解毒，并具有硒非依赖性过氧化物酶活性。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，使用由局部或吸入过敏原激发引起的过敏性气道炎症的良好模型。在整个实验过程中，将采用异前列烷（脂质过氧化的自由基生成产物）的测量来监测体内氧化应激。在第一个具体目标中，我们将确定GSTP1的遗传变异体是否差异调节气道中过敏原引起的氧化应激。在第二个具体目标中，我们将确定抑制气道氧化应激所需的维生素E治疗剂量和时间。有了这些重要的信息，我们将确定补充维生素E是否能调节过敏性哮喘的非特异性气道高反应性和过敏原诱导的支气管痉挛。将这两个具体目标联系起来的问题是，维生素E是否在具有不同GST 1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氧化应激与过敏性哮喘中抗氧化防御关键组分之间复杂相互作用的重要信息。了解抗氧化维生素在哮喘炎症中的作用对于它们在哮喘患者中的适当利用是至关重要的。这项研究将刺激未来对新的预防和治疗方法的研究，重点是抗氧化剂。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，研究设计和分析的先进方法，以及通过实验室和临床培训，课程工作和独立阅读的研究项目管理的高级培训。沿着他的出版物和成就的记录，他将有丰富的学术环境，优秀的导师，和强大的机构承诺，以确保他实现他的目标。(End摘要）

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)