The Albert Einstein College of Medicine (AECOM), the Thomas Jefferson University (TJU) and the University of Minnesota (UMINN) propose to form a member unit of the consortium to develop mouse models for diabetic complications. We propose to contribute mouse models that we have available. In addition, we propose to develop and examine a number of new models for diabetic nephropathy. The Albert Einstein College of Medicine provides Transgenic and Knockout Core Facilities, and Microarray Facilities providing high-density microarrays of cDNA inserts and oligonucleotide arrays. AECOM?s and Philadelphia?s NIH designated Diabetes Research and Training Centers (DRTC) provide other core facilities, including Radioimmunoassay Core, Biochemical Physiology Core and Macromolecular Structure Core that are important phenotyping assets for the proposed work. The AECOM barrier facility where the mice will be developed and housed allow maintenance and breeding of mice in a pathogen-free facility, making it possible to easily ship mice to other facilities. Infrastructure at TJU includes a barrier facility where mice will be made diabetic and a robust histopathology with outstanding expertise on both human and mouse diabetic nephropathy. We have generated/characterized mice with mutations in Lepr (db mutant leptin synaptopodin, Dcn (decorin), and MnSOD (manganese superoxide dismutase). We now propose to validate some of these models. We will generate new transgenic lines to challenge existing models with pathophysiologic genetic modifications in cellular glucose uptake, mitochondrial oxidant injury, podocyte homeostasis, and TGFb activity. We will characterize and validate these models using advanced histopathology and morphometry and gene expression profiling based on microarray technology. Since many of these perturbations are expected to promote diabetic complications in other tissue types as well, it is possible that combining our gene modifications with those developed by other members of the consortium may provide for novel models of range of diabetic complications in humans.
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