Within the context of this renewal application, project 1 focuses on the previously established connection between a variety of mouse models with genetic defects in nucleotide excision repair and the segmental progeroid phenotype exhibited by these mutants (and the corresponding human patients). Complementary to project 4, project 1 addresses the impact of helix-distorting DMA damage on onset, progression and type of ageing and how it triggers a 'survival'response that normally is associated with longevity. We identified this response recently by gene expression profiling. In the current proposal we would like to capitalize on the mouse mutants for addressing 3 specific aims. First, in collaboration with project 3 we intend to extract valuable biomarkers and extend these to the human condition (together with project 5). These will be invaluable for early detection and proper diagnosis of ageing-related pathology, which is essential for the design of effective prevention strategies, for accurate prognosis, and for monitoring modalities for intervention and therapy. The wide spectrum of ageing-associated diseases exhibited by our progeroid mice allows discovery of markers for many different ageing-related pathologies. Secondly, we plan to use the rapidly aging mutant mice and derived cell lines for the design of cellular reporter assays for the screening of intervention molecules that either alleviate the induction of DMA damage or improve the cellular and organismal response to it (e.g. trigger the 'survival'response). For this we will utilize the detailed gene expression profiling data we have collected that is specific for ageing pathology and the 'survival'response towards genotoxic stress and combine different elements of gene expression (transcription as well as microRNA-mediated regulatory elements) to obtain a maximal dynamic range for the assay. The final objective is to employ a novel knock-in mouse model expressing a fluorescent repair protein in all organs and tissues. In combination with sophisticated single cell repair assays we plan to use the mouse knock-in to examine whether or not DNA repair potency declines in ageing and if so how, whether it is stochastic (cf. project 2). Thus project 1 has multiple links with all other projects of the programme.

Public Health Relevance

Ageing and ageing-associated diseases are one of the major challenges for health care in industrialized societies. For early detection, prevention and therapy understanding of the molecular basis of ageing is a prerequisite. We have established a strong link between damage to our genes and onset of ageing-related pathology using mouse mutants. These mice will be used as platform for detection of valid biomarkers, for screening for compounds that delay ageing-related diseases and for increasing our insight.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG017242-16
Application #
8437200
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$208,805
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Hernandez-Segura, Alejandra; de Jong, Tristan V; Melov, Simon et al. (2017) Unmasking Transcriptional Heterogeneity in Senescent Cells. Curr Biol 27:2652-2660.e4
Milholland, Brandon; Suh, Yousin; Vijg, Jan (2017) Mutation and catastrophe in the aging genome. Exp Gerontol 94:34-40
Dong, Xiao; Zhang, Lei; Milholland, Brandon et al. (2017) Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat Methods 14:491-493
Vijg, Jan; Dong, Xiao; Zhang, Lei (2017) A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden. Exp Biol Med (Maywood) 242:1318-1324
Baar, Marjolein P; Brandt, Renata M C; Putavet, Diana A et al. (2017) Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell 169:132-147.e16
Ogrodnik, Mikolaj; Miwa, Satomi; Tchkonia, Tamar et al. (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691
Milholland, Brandon; Dong, Xiao; Zhang, Lei et al. (2017) Differences between germline and somatic mutation rates in humans and mice. Nat Commun 8:15183
Andriani, Grasiella A; Vijg, Jan; Montagna, Cristina (2017) Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain. Mech Ageing Dev 161:19-36
Lau, Cia-Hin; Suh, Yousin (2017) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology 63:103-117
Perrott, Kevin M; Wiley, Christopher D; Desprez, Pierre-Yves et al. (2017) Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience 39:161-173

Showing the most recent 10 out of 244 publications