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: 8010970
• 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/8010970
• 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.

项目总结（见说明）： 这是一份申请，旨在为候选人激活独立之路奖的ROO阶段， 追求独立的研究生涯，研究炎症和氧化应激的机制， 呼吸道疾病，如哮喘。哮喘影响着全球3亿人， 到2025年将超过4亿人。更好地理解生理机制 这种疾病的病理基础将是确定新的治疗方法的关键， 改善临床结果。炎症在哮喘的发病机制中起着核心作用。一个重要的：蚂蚁 炎症介质是一氧化氮（NO），一种支气管循环的血管扩张剂。最近的研究表明 哮喘可能是一种NO生物利用度降低的疾病。NO是由L-精氨酸（L-arg）通过 一氧化氮合酶（NOS）。最近有报道，哮喘患者L-arg生物利用度降低， 可能导致哮喘中NO缺乏。不对称二甲基精氨酸（ADMA），一种内源性 一氧化氮合酶抑制剂，已被确定为一种新的心血管危险因素， 在各种疾病中报告。尽管临床和实验证据表明， ADMA可能导致相对的L-arg缺乏，关于哮喘患者ADMA水平的数据很少。 我们最近的数据支持这样的观点，即ADMA在气道炎症的小鼠模型中发生了改变， 升高的ADMA有助于在这些模型中观察到的病理学。因此，建议的研究 本研究的主要目的是：（1）阐明ADMA诱导的细胞凋亡的机制和后果 氧化和亚硝化应激;（2）阐明ADMA在肺组织中的作用， 上皮细胞，和（3）确定ADMA升高的机制，在小鼠模型的气道 炎症在这项建议成功完成后，我们期望这些研究将提供 将这项工作扩展到人类研究所需的信息，并可能最终导致 确定新的治疗策略。