Polymorphisms of Neural NOS and the Asthma Phenotype

神经 NOS 多态性与哮喘表型

• 批准号: 6320982
• 负责人: MICHAEL E WECHSLER
• 金额: $ 13.39万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-05 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6320982
• 关键词: asthma; genetic polymorphism; genetic susceptibility; human subject; nitric oxide; nitric oxide synthase; nucleic acid repetitive sequence; patient oriented research; respiratory gas level; respiratory hypersensitivity

DESCRIPTION (provided by applicant) Nitric oxide (NO) is a potent bioactive mediator that has been implicated in the pathogenesis of asthma as it has been noted to have both proinflammatory and bronchodilatory effects. Clinically, it is well established that levels of mixed expired NO are, on average, considerably higher in patients with asthma than in nonasthmatics. However, a wide spectrum of heterogeneity exists among asthmatics in terms of levels of expired NO. NO is formed in the lung by a family of enzymes known as the nitric oxide synthases, and allelic variations of NOS1, the gene for neural nitric oxide synthase (type I NOS) on chromosome l2q, have been identified and associated with asthma. Animal studies have documented that targeted disruption of NOS1 resulted in lower levels of exhaled NO and decreased airway hyperresponsiveness following allergen challenge, thus demonstrating the potential importance of NOS1 in asthma pathogenesis. A potential role of NOS1 in asthma pathogenesis and heritability derives from the fact that one of the recently described NOS1 polymorphisms consists of intronic trinucleotide tandem repeats that are similar to the repeat sequences that have been implicated in the pathogenesis of several neurologic disorders including Huntington?s Disease. Preliminary human studies reviewed herein suggest that mild asthmatics who harbor NOS1 alleles with a greater number of intronic trinucleotide repeats have lower and less variable levels of expired NO. This association has been replicated in patients with cystic fibrosis. These observations prompt the following hypothesis: Polymorphisms of NOS1 are associated with variable levels of exhaled NO and airway hyperresponsiveness in subjects with asthma; these allelic variations in NOS1 with resultant variable NO production manifest as significant distinct asthma phenotypes with variable clinical features representing important clues to the genetic diversity of asthma. To test this hypothesis, we propose three specific aims. In the first specific aim, we will determine the relationship between genotype at the NOS1 locus, baseline lung function and mixed expired NO in a cohort of patients with mild-to-moderate asthma. If our hypothesis is correct, we expect to demonstrate that asthmatics harboring allelic variants with greater number of repeats excrete less NO in their exhaled breath and are relatively hyporesponsive to non-specific bronchoprovocative maneuvers as compared to asthmatics with similar clinical characteristics whose alleles harbor fewer repeats. In the next two specific aims, we will study the response of a cohort of subjects with asthma with different NOS1 polymorphisms to specific clinical interventions, including bronchoprovocation with allergen inhalation, bradykinin challenge, hypertonic saline challenge and withdrawal of inhaled corticosteroids. We expect to demonstrate that subjects harboring different NOS1 alleles will have differential responses to these various challenges. We hope that completion of these specific aims will help us understand the role of nitric oxide as a mediator and indicator of asthmatic airway inflammation, how genetic differences influence these roles, and how neural mechanisms may contribute to the pathophysiology and symptomatology of asthma.

描述(由申请人提供) 一氧化氮(NO)是一种强有力的生物活性介质，已被认为与 哮喘的发病机制已被注意到既有促炎作用 以及扩张支气管的作用。在临床上，已经很好地确定了 在哮喘患者中，混合过期一氧化氮的平均水平要高得多 而不是非哮喘患者。然而，它们之间存在着广泛的异质性 哮喘患者血中过期NO的水平。一氧化氮是在肺中由一种 一氧化氮合酶家族及其等位基因变异 NOS1，染色体上的神经型一氧化氮合酶(I型NOS)基因 L2q已被发现并与哮喘有关。动物研究表明 有记录表明，对NOS1的定向干扰导致了较低的 呼出一氧化氮并降低过敏原引起的呼吸道高反应性 挑战，从而表明NOS1在哮喘中的潜在重要性 发病机制。NOS1在哮喘发病机制和遗传性中的潜在作用 源于最近描述的NOS1多态之一 由内含子三核苷酸串联重复组成，类似于 与几种疾病的发病有关的重复序列 神经系统疾病包括亨廷顿病、S病。初步人体研究 本文综述表明携带NOS1等位基因的轻度哮喘患者 内含子三核苷酸重复次数越多，变量越小 过期编号水平。这种关联已经在患有 囊性纤维化。这些观察结果引发了以下假设： NOS1基因的多态与呼出的NO和 哮喘受试者的气道高反应性；这些等位基因变异 在结果变量为NO的NOS1中，生产表现为显著不同 具有不同临床特征的哮喘表型代表重要线索 哮喘的遗传多样性。为了检验这一假设，我们提出了三个假设 明确的目标。在第一个具体目标中，我们将确定两国关系 NOS1基因座的基因型、基线肺功能和混合型失效之间 在一组轻到中度哮喘患者中没有。如果我们的假设是 正确，我们希望证明哮喘患者携带等位基因变异 随着重复次数的增加，呼出的呼吸中排出的NO更少， 对非特异性支气管刺激动作的相对低反应性，如 与临床特征相似的哮喘患者的等位基因比较 减少重复次数。在接下来的两个具体目标中，我们将研究 一组不同NOS1基因多态性的哮喘患者的反应 对特定的临床干预，包括用变应原激发支气管 吸入、缓激肽激发、高渗盐水激发和戒断 吸入的皮质类固醇。我们希望证明研究对象藏匿在 不同的NOS1等位基因会对这些不同的 挑战。我们希望，完成这些具体目标将帮助我们 理解一氧化氮作为哮喘的介质和指示物的作用 呼吸道炎症，遗传差异如何影响这些角色，以及如何 神经机制可能与其病理生理学和症状学有关。 哮喘。