Molecular pathways leading to chronic graft dysfunction

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DESCRIPTION (provided by applicant): Loss of kidney graft function with tubular atrophy (TA) and interstitial fibrosis (IF), a set of findings termed chronic allograft nephropathy (CAN), causes most kidney allograft losses and remains a significant clinical challenge in kidney transplantation (KTx). Discerning the initial molecular events that predispose and trigger CAN represents the best design for improving long-term graft survival rates. Our long-term goal is to determine how the distinct and identifiable factors causing CAN affect the molecular pathways in the graft that progressively lead to chronic allograft dysfunction. The specific hypothesis is that the elucidation of correlations between gene expression profiles and progression to CAN in kidney transplant patients will allow the identification and use of biomarkers in non-invasive assays for early diagnosis and the recognition of possible therapeutic options through the discovery of causal mechanisms. We base the hypothesis on the observations that 1) underlying triggers for CAN may in fact be impossible to decipher, when the graft is sampled with established injury and, 2) many of the pathways involved in chronic allograft injury and fibrogenesis might be regulated very early in the course of the injury when the downstream effects of these alterations are still not evident by pathology. Therefore, these observations justify a role of early graft sampling by microarray technology to identify early molecular markers for CAN disease progression. We will test our hypothesis by carrying out experiments directed at the following specific aims: 1- To elucidate the genes associated with the progression to chronic graft dysfunction in kidney transplant allografts for both the development of useful biomarkers to predict CAN and for the elucidation of causal mechanisms of CAN. We will prospectively study gene expression profiling in graft biopsies at pre-implantation, post reperfusion and during the first 9 months post-KTx. 2-To demonstrates that differential gene expression in peripheral blood mononuclear cells (PBMC) or/and urine cells (non-invasive monitoring) are related to the changes observed in the renal allograft biopsies (invasive monitoring) during progression to CAN. We will study differences that exist in the kidney allograft, urine samples and in PBMC using gene expression strategies for identifying new non-invasive biomarkers. 3-To prospectively establish the clinical utility of using the selected biomarkers in the early diagnosis and prognosis of CAN. We will use real time-RT-PCR in PBMC and urine samples employing a limited panel of markers in an independent group of patients to test the predictive value of these new biomarkers. We will demonstrate that this panel of biomarkers can predict early changes leading to CAN, which can be useful in managing the patient and in designing more sophisticated hypothesis driven experiments to directly test possible causal mechanisms of CAN. PUBLIC HEALTH RELEVANCE: Despite of progresses in immunosuppression, chronic allograft nephropathy (CAN) causes most kidney allograft losses and remains the main clinical challenge for improving long-term graft survival rate. The pathophysiology of CAN remains poorly understood and requires further prospective study using human allograft tissue. Discerning the initial molecular events that predispose and trigger CAN represents the best design for improving long-term graft survival rates.