(Taken directly from the application) The renin-angiontensin system (RAS) is a key regulator of blood pressure and fluid homeostasis. While these hemodynamic functions have been long recognized, the RAS also has a number of non-hemodynamic actions that are important in pathological states such as congestive heart failure and chronic renal disease. In preliminary studies, we have identified a novel action of angiotensin II as a pro-inflammatory mediator that is activated during alloimmune responses. Based on these observations, we hypothesize that angiotensin II, acting through the type I (AT1) class of angiotensin receptors, functions as a T cell cytokine. We posit that these actions contribute to the pathogenesis of allograft rejection and AT1 receptor antagonism may have a role in the treatment of allograft rejection. This hypothesis will be tested using genetically altered mice in studies progressing from isolated preparations of lymphocytes to whole animal models of transplantation in the following specific aims:
Specific Aim I : To characterize the ability of angiotensin II to augment T cell activation in an alloimmune response.
Specific Aim II : To define the intra-cellular signaling pathways used by angiotensin II to promote T cell proliferation.
Specific Aim III : To identify the sources and regulation of angiotensin II production by the immune system.
Specific Aim I V: To determine the efficacy of AT1 receptor blockade in information regarding the role of the renin-angiotensin system in immune responses such as allograft rejection. Furthermore, these experiments may provide the basis for new therapeutic approaches to prevent allograft injury without increasing immunosuppressive burden. We will attempt to define a molecular rationale for AT1 receptor blockade as a therapy in allograft rejection.
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