(Taken directly from the application) The aim of this Program Project is to investigate mechanisms of kidney graft dysfunction using an experimental model of renal transplantation. Since its inception, studies in the program have been based on the premise that allograft rejection is a complex inflammatory response that generates effector elements which cause graft dysfunction and injury. Each project focuses on the role of elements, either constitutive to the kidney graft or produced within the graft during rejection, which influence with inflammatory response. The structure of the program has been developed in recognition of the interdependence of these elements and the projects are linked both in thematic content and through the interactions and complementing expertise of the investigators. In Project #1 transplantation will be explored. These studies will highlight the role of angiotensin II as an inflammatory mediator in rejection, exploring its effects to modulate T cell activation and promote kidney injury. The role of mice that are deficient in Type 1 (AT1) angiotensin II receptors. Project #2 (Principal Investigator: J. Ting) will continue one of the ongoing themes in the pathogenesis of rejection. These studies will focus on the role of class II MHC in regulating tissue injury. Using mice with targeted mutations in genes that are involved in expression of class II MHC proteins, these studies will explore the role of the master transcription factor CIITA as a potential therapeutic target in rejections responses. In Project #3 (Principal Investigator: B. Koller), ongoing studies to further define the role of studies take advantage of a series of mouse lines, developed during the previous funding period, which lack key enzymes involved in leukotriene actions in a variety of responses including allograft rejection. Through the successful completion of these studies, this Program Project will continue to unravel the mechanisms of kidney transplant dysfunction in rejection with the goal of providing new diagnostic and therapeutic approaches to current problems in clinical transplantation.
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