Inflammatory disorders account for a significant proportion of disabling and life-threatening disease. For example, heart disease, chronic lower respiratory diseases, sepsis, and hypertension/hypertensive renal disease accounted for 28%, 5.2%, 1.4%, and 0.9%, respectively, of all deaths in the US in 2003. Dramatic changes in arginine metabolism occur in inflammation and injury as a result of changes in activity or expression of the nitric oxide synthases (NOS) and the arginases. There is considerable evidence that increases in arginase activity can contribute to the pathophysiologic consequences of inflammation. However, the precise contributions of changes in arginase activity and expression to inflammatory disease processes are not fully understood, thus limiting rational development of therapeutic strategies. The arginases are of particular interest because they can affect the synthesis not only of NO but also of polyamines and proline, which are essential for cell proliferation and collagen synthesis, respectively. The latter processes are involved not only in wound healing but also in fibrotic complications of chronic inflammation, such as vascular remodeling. Our understanding of the role and regulation of arginase activity in these processes is complicated by the existence of two arginase isozymes that are independently regulated, as well as by absence of information regarding expression of arginine transporters and other enzymes that use and produce arginine metabolites. In order to elucidate the roles of the individual arginase isozymes in vivo and in specific cell types, this proposal will use mouse strains in which expression of individual arginase isozymes has been selectively ablated or overexpressed in specific cell types. The following aims will test specific hypotheses regarding the roles of each arginase isozyme in vivo and in specific cell types during responses to inflammatory stimuli:
AIM I. Elucidate the contributions of each arginase isozyme in in vivo models of acute and chronic inflammation.
AIM II. Elucidate the metabolic roles of each arginase isozyme in macrophages and endothelial cells in inflammation.
AIM III. Elucidate mechanisms by which increased arginase activity alters expression of specific genes. OUTCOME: Results of these studies will provide a basis for development of tests for rational development of new and more effective therapeutic strategies and for monitoring efficacy of treatment in diseases in which arginases play a role.
It is now recognized that increases in activities and expression of the arginase isoenzymes can contribute to development or progression of many inflammatory diseases. However, the mechanisms whereby the increases in arginase activity contribute to the initiation and progression of disease are not fully understood. The objective of this proposal is to elucidate the roles of the individual arginase isoenzymes in multiple models of inflammation in mice and in cultured cells. Results of these studies will provide a basis for rational development of new and more effective therapeutic strategies and for monitoring efficacy of treatment in inflammatory diseases.
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