The role of ADMA in the pathology of asthma

描述（由申请人提供）： 这是一个申请独立之路奖的候选人追求独立的研究生涯，研究哮喘病理学中的炎症和氧化应激机制。哮喘影响全球3亿人，预计到2025年将影响超过4亿人。更好地了解这种疾病的病理基础的生理机制将是至关重要的，在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。一种重要的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NO生物利用度降低的一种情况。 NO由L-精氨酸（L-arg）通过NO合酶（NOS）产生。最近有报道，哮喘患者L-arg生物利用度降低可能导致哮喘患者NO缺乏。不对称二甲基精氨酸（ADMA）是一种内源性NOS抑制剂，已被确定为一种新的心血管危险因素，其蓄积已被报道在各种疾病中。 虽然临床和实验证据表明，ADMA的升高可能会导致相对的L-arg缺乏症，没有数据可在哮喘患者的ADMA水平。因此，拟议的研究将集中在以下具体目标：（1）阐明ADMA诱导的氧化和亚硝化应激的机制和后果;（2）描述ADMA在改变的呼吸酶功能中的作用;（3）利用小鼠模型证明ADMA水平改变对气道高反应性、炎症和气道重塑发展的体内影响。在成功完成这项提案后，我们的期望是，这些研究不仅将为哮喘的病理学提供新的见解，而且还可能确定疾病发展的新因素。此外，这些研究的数据将提供必要的信息，将这项工作扩展到人类研究，并可能最终导致新的治疗策略的识别。候选人提出的职业发展计划包括先进的动物协议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.