The role of ADMA in the pathology of asthma

ADMA 在哮喘病理学中的作用

• 批准号: 7385484
• 负责人: SANDRA M WELLS
• 金额: $ 9.72万
• 依托单位: UNIVERSITY OF MONTANA
• 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 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385484
• 关键词: Affect; Animals; Arginine; Asthma; Award; Biological Assay; Biological Availability; Blood Circulation; Cardiovascular Diseases; Cells; Characteristics; Chronic; Clinical; Clinical Protocols; Condition; Data; Development; Development Plans; Disease; Elevation; Ensure; Enzymes; Epithelial Cells; Functional disorder; Generations; Goals; Homeostasis; Hyperplasia; Infiltration; Inflammation; Inflammatory; Laboratories; Lung; Mediating; Mediator of activation protein; Mentors; Modeling; Mus; N,N-dimethylarginine; Nitric Oxide; Nitric Oxide Synthase; Numbers; Outcome; Oxidative Stress; Pathogenesis; Pathology; Pathway interactions; Peroxonitrite; Physiological; Play; Pneumonia; Polyamines; Proline; Publishing; Pulmonology; Range; Reaction; Relative (related person); Reporting; Research; Research Personnel; Research Training; Role; Serum; Severities; Stress; Superoxides; Testing; Training; Vasodilator Agents; Work; airway hyperresponsiveness; airway remodeling; arginase; asthmatic patient; base; cardiovascular risk factor; career; concept; design; expectation; human study; improved; in vivo; inhibitor/antagonist; insight; novel; novel therapeutics; programs

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.

描述（由申请人提供）： 这是申请“独立之路奖”的候选人，以从事独立研究职业，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病理学的生理机制对于确定新的治疗方法和改善临床结果至关重要。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)，它是支气管循环的血管扩张剂。最近的研究表明，哮喘可能是一氧化氮生物利用度降低的一种病症。 NO 是由 NO 合酶 (NOS) 从 L-精氨酸 (L-arg) 产生。最近有报道称，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) 是一种 NOS 内源性抑制剂，已被确定为一种新型心血管危险因素，并且已报道其在多种疾病中蓄积。 尽管临床和实验证据表明 ADMA 升高可能导致 L-arg 相对缺乏，但尚无哮喘患者 ADMA 水平的数据。因此，本研究将重点关注以下具体目标：（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 在改变精氨酸酶功能中的作用； (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。在成功完成该提案后，我们期望这些研究不仅将为哮喘病理学提供新的见解，而且有可能确定该疾病发展的新因素。此外，这些研究的数据将提供将这项工作扩展到人体研究所需的信息，并可能最终导致新治疗策略的确定。候选人提出的职业发展计划包括高级动物方案和肺医学临床概念的培训。为了确保候选人实现她的研究和培训目标，她将拥有优秀的导师和顾问、丰富的学术环境和强有力的机构承诺。