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.
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