The role of ADMA in the pathology of asthma

Wells, Sandra

Abstract

? ? 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. ? ? ?