Project #5740
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#5740 : Methylome analysis of a human progeroid disease for the detection of progeroid-specific alterations and their link with regular ageing
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Name of Applicant : Miria Ricchetti
Date of application : 02-05-2016
Unit : Stem Cells And Development
Location : Monod (66) - 4 - 19
Phone : 0145688567
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Project context and summary :

The mechanisms governing ageing, which is a multifactorial process, have not been resolved and constitute a fundamental open question in cell and organismal biology. Exceptionally, in rare genetic diseases like the Cockayne syndrome (CS), ageing is dramatically accelerated. We have recently identified a novel pathway that is altered in cells from CS patients and is not affected in a linked disease (UVSS) that is not associated with precocious ageing. This is a unique case in the literature of diseases due to mutations in the same proteins but only one resulting in precocious ageing. The defect linked to the progeroid phenotype consists in oxidative stress-dependent overexpression of a little known proteases, HTRA3, which degrades the key mitochondrial DNA polymerase and in turn affects mitochondrial function. We succeeded in rescuing the defective phenotype in patient cells using two independent strategies. We aim to understand the mechanism by which oxidative stress induces overexpression of HTRA3 and we have indications that this event may be linked to the methylation of target genes. Genome wide methylation will be analysed in these rare patient cells.

Related team publications :
Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome. Chatre L, Biard DS, Sarasin A, Ricchetti M. Proc Natl Acad Sci U S A. 2015 Jun 2;112(22):E2910-9. doi: 10.1073/pnas.
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Project Type : Medium
Status : Awaiting Publication

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