Evolved metabolic phenotypes for repair in Acomys cahirinus in diabetic nephropathy
Mark Majesky   (Seattle, WA)
Diabetic kidney disease is one of the most severe, progressive, microvascular complications and is the leading cause of end-stage renal disease in the western world. Activation or augmentation of endogenous repair-regeneration pathways represents an optimal treatment strategy to reverse diabetic nephropathy. The wound healing response that characterizes injury and repair-fibrosis is agnostic to the specific injury (diabetes): processes such as oxidative stress, mitochondrial dysfunction, tubular cell death, myofibroblast accumulation and capillary rarefaction, are common to all scar forming, non-regenerative species. A striking exception to this sequence is found in the African spiny mouse (genus: Acomys), a species 20 million years distinct from Mus. Using two models of aggressive renal injury, our preliminary data show that A. cahirinus repairs kidney injuries that are routinely fatal in mice (M. musculus) without fibrosis and restores essentially normal kidney function. In this application, we will use A.cahirinus as discovery tool to identify novel endogenous repair-regeneration pathways that can then be applied to established diabetic nephropathy models. Comparing genome-wide transcriptional responses between scar-resistant (A. cahirinus) and scar-forming (M. musculus) wound healing in this DiaComp project is a necessary and important step to developing novel therapeutic approaches to better manage or prevent diabetic kidney disease.
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