The role of asymmetric dimethylarginine (ADMA) in asthma

项目总结(见说明)： 这是一个应用程序，用于激活候选人的独立途径奖的Roo阶段 从事研究炎症和氧化应激机制的独立研究工作 呼吸道疾病，如哮喘。哮喘影响全球3亿人，预计将影响 到2025年，人口将超过4亿。对生理机制有更好的了解 了解这种疾病的病理基础将是确定新的治疗方法和 改善临床结果。炎症在哮喘的发病机制中起着核心作用。一位重要人物：蚂蚁 炎症介质是一氧化氮(NO)，是一种支气管循环的血管扩张剂。最近的研究表明 哮喘可能是一种生物利用度降低的情况。NO是由L-精氨酸(L-Arg)由 没有合酶(NOS)。最近有报道称，L精氨酸在哮喘患者中的生物利用度降低 可能与哮喘的NO缺乏有关。内源性不对称二甲基精氨酸(ADMA) 一氧化氮合酶抑制物已被确定为一种新的心血管危险因素，其积聚已被 报道了各种疾病。尽管临床和实验证据表明， ADMA可能导致相对的L-精氨酸缺乏，有关哮喘患者ADMA水平的数据很少。 我们最近的数据支持这样的观点，即ADMA在小鼠呼吸道炎症模型中是改变的，并且 ADMA升高是这些模型中观察到的病理改变之一。因此，拟议的研究 将集中于以下具体目标：(1)阐明ADMA诱导的机制和后果 氧化和亚硝化应激；(2)ADMA在肺内精氨酸酶功能改变中的作用 (3)探讨ADMA升高的机制。 发炎。在成功完成这项建议后，我们预期这些研究将提供 将这项工作扩展到人体研究所需的信息，并可能最终导致 确定新的治疗策略。

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.