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Epigenetic modifications in glomerular nephropathy and renal aging (RENAL EPIGENETICS)
Date du début: 1 sept. 2011, Date de fin: 11 nov. 2018 PROJET  TERMINÉ 

Here, we propose a program to identify the role of mTOR and autophagy dependent epigeneticmodifications during kidney aging. We have assembled a unique set of complementary mouse models including kidney specific and timely inducible autophagy and mTOR deficient mice. For the detailed molecular analysis of transgenic podocyte tissue, we have generated a double-labeled transgenic mouse model, where podocytes expressing green fluorescent protein are contrasted by other kidney cells expressing red fluorescent protein. Using this mouse model, we have pioneered a cell sorter based purification of glomerular podocytes from kidney single cell suspensions, which allows us to perform the first epigenetic analysis of aged and transgenically modified podocytes. mTOR and / or autophagy dependent gene expression signatures, histone modifications and chromatin-remodeling patterns associated with kidney aging in transgenic and wildtype mice will be identified. We recently showed that mTOR hyperactivation at early stages of diabetic nephropathy determines the progressive course of the disease. We now hypothesize that transient mTOR hyperactivation may induce epigenetic modifications representing the clinically observed, but still unresolved “metabolic memory” of diabetic nephropathy. Insummary, this project aims to elucidate fundamental biological mechanisms of kidney aging. This may ultimately aid in risk prediction and improved targeted medical interventions to promote healthy aging and to prevent chronic kidney diseases such as diabetic nephropathy.