The role of ADMA in the pathology of asthma

描述(由申请人提供)： 这是一份独立途径奖的申请书，候选人将继续从事研究炎症和氧化应激在哮喘病理中的机制的独立研究事业。哮喘影响着全球3亿人，预计到2025年将超过4亿人。更好地了解这种疾病的病理基础的生理机制将是确定新的治疗方法和改善临床结果的关键。炎症在哮喘的发病机制中起着核心作用。一种重要的炎症介质是一氧化氮(NO)，它是一种支气管循环的血管扩张剂。最近的研究表明，哮喘可能是一种无生物利用度降低的状况。一氧化氮是由L精氨酸(L精氨酸)通过一氧化氮合酶(NOS)产生的。最近有报道称，哮喘患者体内L-精氨酸生物利用度降低可能与哮喘患者体内NO缺乏有关。一氧化氮合酶(NOS)内源性抑制物不对称二甲基精氨酸(ADMA)是一种新的心血管危险因子，其在多种疾病中的蓄积已有报道。虽然临床和实验证据表明ADMA升高可能导致相对的L-精氨酸缺乏，但目前还没有关于哮喘患者ADMA水平的数据。因此，本研究将集中于以下具体目标：(1)阐明ADMA诱导的氧化和亚硝化应激的机制和后果；(2)阐明ADMA在改变精氨酸酶功能中的作用；(3)利用小鼠模型证实ADMA水平改变对气道高反应性、炎症和气道重塑的体内影响。在成功完成这项提议后，我们期望这些研究不仅将为哮喘的病理提供新的见解，还可能确定疾病发展的新因素。此外，来自这些研究的数据将提供必要的信息，将这项工作扩展到人体研究，并最终可能导致确定新的治疗策略。候选人提出的职业发展计划包括高级动物方案和肺部医学临床概念的培训。为了确保候选人完成她的研究和培训目标，她将有一个优秀的导师和顾问，丰富的学术环境，以及强大的机构承诺。

DESCRIPTION (provided by applicant): This is an application for a Pathway to Independence Award for the candidate to pursue an independent research career studying the mechanisms of inflammation and oxidative stress in the pathology of asthma. Asthma affects 300 million people worldwide and is predicted to affect over 400 million people by the year 2025. A better understanding of the physiological mechanisms underlying 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 important inflammatory mediator is nitric oxide (NO), a vasodilator of the 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, no data are available on the ADMA levels in asthmatic patients. Therefore, the proposed research will focus on the following specific aims: (1) to elucidate the mechanism and consequences of ADMA-induced oxidative and nitrosative stress; (2) to delineate the role of ADMA in altered arginase function, and; (3) to demonstrate an in vivo effect of altered ADMA levels on the development of airway hyperresponsiveness, inflammation, and airway remodeling utilizing murine models. Upon successful completion of this proposal, our expectation is that these studies will not only provide new insights into the pathology of asthma, but also potentially identify a novel factor in the development of the disease. Furthermore, data from 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. The candidate's proposed career development plan includes training in advanced animal protocols and clinical concepts in pulmonary medicine. To ensure that the candidate accomplishes her research and training goals, she will have an excellent mentor and advisors, rich academic surroundings, and strong institutional commitment.