Murine-HumanTranscriptomic Comparisons in Diabetic Nephropathy and Neuropathy
Comparison of genome-wide transcriptional profiles obtained from human and murine diabetic nephropathy (DN) and polyneuropathy (DPN) should allow identification of diabetic endorgan damage mechanisms that are conserved between mice and humans as well as those that are important in humans but whose absence in mice impairs development of full-blown DN or DPN. Targeting these pathways should greatly facilitate translation of findings from animal models to human disease and the development of improved murine models of DN and DPN.

Cross-Species Systems Biology of Diabetic Nephropathy
Diabetic nephropathy (DN) is an endorgan complication responsible for significant morbidity and mortality in type 1 and type 2 diabetes mellitus. Association of genes and gene products with DN are currently defined in humans using genome wide association studies and renal tissue based gene expression studies. However, animal models are instrumental to define the functional impact of the associated molecules. The AMDCC has established an extensive data set defining the framework for DN in mice. A crucial next step will be to integrate the murine molecular information with corresponding comprehensive human data sets. We have developed and employed a webbased analysis engine, Nephromine, for integrated systems biology analysis of renal gene expression for the renal research community. Nephromine accesses highly annotated human renal gene expression datasets in multiple search modes (see tutorial at nephromine.org), though Nephromine has been limited to human datasets to date. The goal of this application is to integrate murine DN gene expression data sets generated by the AMDCC and the renal research community at large with the human DN data sets to define shared and specific mechanism between mouse and man. Specific aims to be addressed are: Aim 1. Identify and annonate murine gene expression data sets of DN from AMDCC data repository, Gene Expression Omnibuts (GEO) and those accessed by direct interaction with investigative teams. Aim 2. Compare murine DN gene expression data sets with human DN data sets and identify shared transcriptional changes on a network level. Aim 3. Upload murine data sets into Nephromine for human-mouse comparative analysis by the renal research community. Comparing the renal transcriptiome of human DN to the carefully characterized AMDCC murine DN models will allow the renal research community to define molecular mechanism shared between mouse and man. With this information, investigators will be able to select the murine models that recapitulate the human disease mechanisms to be interrogated in their murine experimental studies. Defining mouse models a priori for their ability to recapitulate human disease will be a crucial step to increase comparability of murine studies to human disease mechanisms. This will aid in defining novel therapeutic targets for their efficacy in the specific murine models of DN and should decrease the attrition rate of compounds with activity in murine DN in their further validation as therapeutic targets of human DN.

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