(PROJECT 2) The overarching theme of the Program Project Grant (PPG) is that spontaneous DNA damage drives major components of aging by causing DNA mutations and eliciting adverse cellular responses, e.g., apoptosis, cellular senescence. The central hypothesis of Project 2 is that low levels of the highly toxic DNA double-strand breaks (DSBs) are a cause of aging, both through cellular end points and through DNA mutations. In the new Project 2 we will test this hypothesis by studying the role of DSBs in promoting the molecular and cellular phenotypes associated with aging. In two specific aims we will (1) further analyze the pro-aging effects of DSBs in WT and Ercc1-/?7 and Ku80-/- mice and (2) comprehensively determine the landscape of somatic mutations in liver of WT and Ercc1-/?7 and Ku80-/- mice, with a focus on genome structural variations that typically result from erroneous repair of DSBs. We will also test if the pro-longevity interventions developed by our collaborators do not only affect survival of cells and tissues, but also prevent or dampen genome instability.
(PROJECT 2) Project 2 of this proposed program project renewal will test the causal role of the highly toxic DNA double- strand breaks in aging and age-related pathology. It is expected that the results will bring us closer to understand the mechanisms of aging and disease and provide new starting points for the development of interventions to promote healthy aging and longevity.
|Lau, Cia-Hin; Suh, Yousin (2018) In vivo epigenome editing and transcriptional modulation using CRISPR technology. Transgenic Res 27:489-509|
|Wiley, Christopher D; Schaum, Nicholas; Alimirah, Fatouma et al. (2018) Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Sci Rep 8:2410|
|Quispe-Tintaya, Wilber; Lee, Moonsook; Dong, Xiao et al. (2018) Bleomycin-induced genome structural variations in normal, non-tumor cells. Sci Rep 8:16523|
|Hébert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279|
|Yu, Bo; Dong, Xiao; Gravina, Silvia et al. (2017) Genome-wide, Single-Cell DNA Methylomics Reveals Increased Non-CpG Methylation during Human Oocyte Maturation. Stem Cell Reports 9:397-407|
|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|
|Ogrodnik, Mikolaj; Miwa, Satomi; Tchkonia, Tamar et al. (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691|
|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|
|Olivieri, Fabiola; Capri, Miriam; Bonafè, Massimiliano et al. (2017) Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev 165:162-170|
|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 253 publications