A Novel Mouse Model of Podocyte Injury

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DESCRIPTION (provided by applicant): A novel mouse model of podocyte injury: Genetic studies have highlighted the importance of glomerular epithelial cells (podocytes) in the development of glomerular disease processes. Moreover, recent studies suggest an important role for podocyte depletion in the pathogenesis of acquired glomerular diseases such as diabetic nephropathy. Indeed, accumulating evidence suggests that podocyte depletion may be a final common pathway causing progressive renal injury characteristic of glomerular disease processes. The ability of investigators to study glomerular diseases has been significantly enhanced by the use of genetically manipulated animals. Preeminent among these genetically manipulated animals are mice which have become the animals of choice for performing genetic manipulations in vertebrates. Unfortunately, mice are resistant to many of the glomerular disease models developed in rodents. This limitation has significantly impaired the ability of investigators to study glomerular disease processes using genetically manipulated mice. In response to the Program Announcement (PA-07-012) entitled, "Animal models of NIDDK-relevant diseases", we propose to develop a mouse model of podocyte injury that will permit reproducible and graded degrees of podocyte damage. The proposed model should facilitate the preclinical testing of diagnostic, preventive and/or therapeutic interventions in glomerular diseases and, therefore, the proposed experiments are directly relevant to this Program Announcement. For the experiments, we will use the podocyte specific podocin promoter to target expression of the yeast enzyme cytosine deaminase (CD) to glomerular epithelial cells. This enzyme catalyzes the conversion of the drug 5- flucytosine (5-FC) to 5-fluorouracil (5-FU), a metabolite that inhibits both DNA and RNA synthesis and, in turn, promotes death in cells that are not activity dividing such as podocytes. In the proposed studies, we will 1. Create transgenic (TG) mice expressing CD specifically in glomerular podocyte and determine the dose dependent ability of 5-FC produce podocyte injury as well as reversibility of the podocyte damage, and 2. Test the role of podocyte depletion in augmenting glomerular injury in a genetic model of type 1 diabetes mellitus by crossing CD TG animals with Akita mice. The successful development of the proposed mouse model will permit investigators to test preventive and/or therapeutic interventions in diseases caused by podocyte injury as well as to use genetically manipulated mice to identify novel targets for the treatment of glomerular diseases in humans. PUBLIC HEALTH RELEVANCE: Mice are the animals of choice for performing genetic manipulations in vertebrates. Unfortunately, mice are resistant to animal models of kidney disease developed in rodents. This limitation of mouse models has significantly limited the ability of investigators to study kidney diseases using genetically manipulated mice. The goal of this grant application is to develop a mouse model of kidney disease that will facilitate the preclinical testing of diagnostic, preventive and/or therapeutic interventions in kidney diseases using genetically manipulated mice.