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Methods. 2016 Mar 1;96:46-58. doi: 10.1016/j.ymeth.2015.08.024. Epub 2015 Sep 1.

A high-content imaging-based screening pipeline for the systematic identification of anti-progeroid compounds.

Author information

1
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
2
National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
3
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: mistelit@mail.nih.gov.

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is an early onset lethal premature aging disorder caused by constitutive production of progerin, a mutant form of the nuclear architectural protein lamin A. The presence of progerin causes extensive morphological, epigenetic and DNA damage related nuclear defects that ultimately disrupt tissue and organismal functions. Hypothesis-driven approaches focused on HGPS affected pathways have been used in attempts to identify druggable targets with anti-progeroid effects. Here, we report an unbiased discovery approach to HGPS by implementation of a high-throughput, high-content imaging based screening method that enables systematic identification of small molecules that prevent the formation of multiple progerin-induced aging defects. Screening a library of 2816 FDA approved drugs, we identified retinoids as a novel class of compounds that reverses aging defects in HGPS patient skin fibroblasts. These findings establish a novel approach to anti-progeroid drug discovery.

KEYWORDS:

FDA-approved compounds; HGPS; High-content imaging; High-throughput screening; Progerin; Retinoids

PMID:
26341717
PMCID:
PMC6317068
DOI:
10.1016/j.ymeth.2015.08.024
[Indexed for MEDLINE]
Free PMC Article

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