The role of asymmetric dimethylarginine (ADMA) in asthma

不对称二甲基精氨酸 (ADMA) 在哮喘中的作用

• 批准号: 7742702
• 负责人: SANDRA M WELLS
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742702
• 关键词: Affect; Ants; Arginine; Asthma; Award; Biological Availability; Blood Circulation; Blood Vessels; Cardiovascular Diseases; Cell Proliferation; Cell model; Cells; Characteristics; Chronic; Clinical; Collagen; Data; Deposition; Development; Disease; Enzymes; Epithelial; Epithelial Cells; Fibroblasts; Functional disorder; Generations; Homeostasis; Human; Hyperplasia; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Instruction; Laboratories; Lung; Lung diseases; Manuscripts; Mediating; Mediator of activation protein; Modeling; Mus; N,N-dimethylarginine; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Ornithine Decarboxylase; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Peroxonitrite; Phase; Physiological; Play; Production; Protein-Arginine N-Methyltransferase; Proteins; Publishing; Relative (related person); Reporting; Research; Role; Severities; Smooth Muscle Myocytes; Stress; Superoxides; Testing; Vasodilator Agents; Work; airway hyperresponsiveness; airway inflammation; arginase; asthmatic patient; base; cardiovascular risk factor; career; cytokine; design; dimethylargininase; expectation; human NOS2A protein; improved; in vivo; in vivo Model; inhibitor/antagonist; nitrosative stress; novel; novel therapeutic intervention; treatment strategy

PROJECT SUMMARY (See instructions): This is an application to activate the ROO phase of a Pathway to Independence Award for the candidate to pursue an independent research career studying the mechanisms of inflammation and oxidative stress in respiratory diseases such as asthma. Asthma affects 300 million people woridwide and is predicted to affect over 400 million people by the year 2025. A better understanding of the physiological mechanisms underiying the pathology of this disease will be critical in identifying new therapeutic approaches and improving clinical outcomes. Inflammation plays a central role in the pathogenesis of asthma. One impori:ant inflammatory mediator is nitric oxide (NO), a vasodilator ofthe bronchial circulation. Recent studies suggest that asthma may be a condition of decreased NO bioavailability. NO is produced from L-arginine (L-arg) by NO synthase (NOS). It has been recently reported that decreased L-arg bioavailability in asthmatic patients likely contributes to the NO deficiency in asthma. Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NOS, has been established as a novel cardiovascular risk factor and its accumulation has been reported in a variety of disorders. Although clinical and experimental evidence indicates that the elevation of ADMA may cause a relative L-arg deficiency, little data are available on ADMA levels in asthmatic patients. Our recent data support the notion that ADMA is altered in murine models of ainway inflammation and that elevated ADMA contributes to the pathology observed in these models. Therefore, the proposed research will focus on the following specific aims: (1) to elucidate the mechanism and consequences of ADMAinduced oxidative and nitrosative stress; (2) to delineate the role of ADMA in altered arginase function in lung epithelial cells, and; (3) to determine the mechanism of elevated ADMA in murine models of ainway inflammation. Upon successful completion of this proposal, our expectation is that these studies will provide the information necessary to extend this work into human studies and may ultimately result in the identification of novel treatment strategies.

项目摘要（请参阅说明）： 这是激活候选人的独立途径的ROO阶段的应用 从事独立研究职业，研究炎症和氧化应激机制 呼吸系统疾病，例如哮喘。哮喘会影响3亿人，预计会影响 到2025年，超过4亿人。更好地了解生理机制 低于这种疾病的病理，对于确定新的治疗方法和 改善临床结果。炎症在哮喘的发病机理中起着核心作用。一个Impori：蚂蚁 炎症介质是一氧化氮（NO），这是支气管循环的血管扩张剂。最近的研究表明 这种哮喘可能是降低生物利用度的条件。 NO由L-精氨酸（L-arg）产生 无合酶（NOS）。据报道，哮喘患者的L-Arg生物利用度降低 可能导致哮喘的无缺乏。非对称二甲基金融氨酸（ADMA），一种内源性 NOS抑制剂已被确定为一种新型的心血管危险因素，其积累一直是 报告了多种疾病。尽管临床和实验证据表明 ADMA可能会导致相对L-ARG缺乏症，哮喘患者的ADMA水平几乎没有数据。 我们最近的数据支持以下观点：ADA在Ainway炎症的鼠模型中发生了改变，并且 升高的ADMA有助于这些模型中观察到的病理。因此，拟议的研究 将重点介绍以下特定目的：（1）阐明公认所导致的机制和后果 氧化和亚硝化应激； （2）描述ADMA在肺中精氨酸酶功能改变的作用中的作用 上皮细胞，并且； （3）确定Ainway鼠模型中ADMA升高的机理 炎。成功完成该提案后，我们的期望是这些研究将提供 将这项工作扩展到人类研究所需的信息，并最终可能导致 识别新型治疗策略。