Novel Integrated Analyses of Human Diabetic Nephropathy

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is a major source of morbidity and mortality. Both the incidence and prevalence of ESRD secondary to diabetes continue to rise. In the United States, over 30% of patients receiving either dialysis therapy or renal transplantation have ESRD as a result of diabetic nephropathy, and more than 40% of the incident cases of ESRD are attributable to diabetes. Given the global epidemic of obesity in developed countries, an increasing incidence of DN is being widely reported. The underlying pathogenic mechanisms mediating development and progression of human DN are still not well understood. Specifically, there is still incomplete understanding of the nature and etiology of altered protein, lipid and metabolite expression in both the glomerular and tubulointerstitial compartments during the course of human DN, and the spectrum of lesions in patients with diabetes who do not have classic or overt DN is not established because patients do not routinely undergo renal biopsy. To address these gaps in knowledge, we have assembled a team of established and experienced investigators with complementary expertise and a novel set of resources in order to investigate human DN. We will use histology-directed MALDI Imaging Mass Spectrometry (MALDI IMS), a novel imaging technology that has been validated in our preliminary studies of mouse renal tissues, to mine and phenotype proteomic, lipidomic and metabolomic changes in human DN in order to map the molecular profile of lesions that may be attributable to diabetes or to other unrecognized abnormalities in diabetic patients. We will obtain human kidney samples from a cohort of patients pre-consented for DNA analysis and linked to a de-identified electronic medical record (Synthetic Derivative, SD) and DNA samples (BioVU). Validation of a detailed phenotype of patients with existing diabetic nephropathy that continues to be updated in real time will allow detailed prospective mining of such samples. The specific aims of the study are: 1) To create a human kidney tissue biorepository linked to a de-identified electronic medical record in order to facilitate studies of human diabetic nephropathy and other kidney diseases; 2) To determine protein, lipid, and metabolite profiles in distinct nephron segments and cell types in the human diabetic kidney using MALDI IMS and integrate the results with light and electron microscopic findings; 3) To integrate protein, lipid, and metabolite information in the diabetic glomerulus with phenotype and genotype data in order to identify specific molecular changes associated with development or progression of diabetic nephropathy; and 4) To determine potential therapeutic targets by exploring molecular mechanisms underlying the identified changes in proteins, lipids and metabolites occurring in the course of human diabetic nephropathy Our overall goal for these studies is to define the molecular basis for human diabetic nephropathy and to identify potential targets for therapy by utilizing new and powerful modalities: MALDI IMS combined with conventional microscopy and a human renal tissue biorepository linked to both a synthetic medical record and the patients' DNA.