The overall goal of Project 3 is to identify gene expression patterns associated with lung transplant rejection using a new laboratory approach: large scale gene expression microarray (>10,000 genes) technology. We are uniquely positioned to accomplish this by virtue of our active clinical lung transplant program, comprehensive Lung Transplant Database, and the advanced facilities and expertise of the University of Minnesota Biomedical Genomics Center. Acute rejection is common after lung transplantation, occurring in up to 50 per cent of recipients during the first post transplant year. Although it is almost never immediately life threatening, acute rejection is a major risk factor for the later development of chronic lung rejection, or OB, the most important threat to the long-term survival of lung transplant recipients. The statistical relationship between acute and CR exists despite the fact that, in most cases, the histologic findings of acute rejection resolve after treatment. Based on this observation, a fundamental assumption of the proposed research is that specific genes are activated during acute rejection, some of which remain persistently activated despite treatment, and contribute to the pathogenesis of OB. Thus, identification of these genes may serve to identify recipients at risk for CR. In this proposal we will complete two necessary steps toward this goal: 1) identification of specific patterns of gene expression in BAL cells and peripheral blood mononuclear cells that differentiate patients with and without acute lung rejection histology; and 2) identification of genes that are reliably and persistently expressed after treatment induced normalization of acute rejection histology. If successful, these studies will set the stage for additional studies to determine the predictive value of persistently expressed acute rejection associated genes for the subsequent development of CR.
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