Minnesota Nathan Shock Center of Excellence on Genome Integrity and Aging

There is strong evidence that changes in the primary aging hallmark of genomic instability, especially the accumulation of DNA damage and the resulting DNA damage response (DDR) signaling cascade, leads to changes in other hallmarks of aging, including cellular senescence, inflammation, epigenome, proteostasis, dysbiosis, and mitochondrial and stem cell dysfunction. Thus, there is a clear need to be able to quantitate and characterize the extent of DNA damage and DDR signaling comprising a key primary hallmark of aging and to quantitate DNA repair activity. The goal of this Minnesota (MN) Nathan Shock Center of Excellence on Genome Integrity and Aging (MN NSC) is to provide access to cores with the ability to accurately measure specific endogenous DNA adducts reflecting oxidative and metabolic stress in genomic DNA, the signaling associated with the DDR, including markers of senescence, and the extent of DNA repair activity as well as measure certain DNA methylation epigenetic changes associated with DNA damage and age. Also, the MN NSC will provide access to murine and human cells and tissues and mice with reduced DNA repair capacity and increased DNA damage, senescence and other hallmarks of aging. In addition, the MN NSC will provide access to mouse models with accelerated DNA damage for testing of agents for their ability to reduce DNA damage and/or the effects of DDR on other aging hallmarks. To accomplish this, the MN NSC will leverage existing resources and strong institutional support within the new UMN Institute on the Biology of Aging and Metabolism (iBAM) as well as the University of Minnesota (UMN). The MN NSC and the Administrative and Program Enrichment Core (A/PEC) A are co-directed by Drs. Paul Robbins and Laura Niedernhofer, Co-Directors of iBAM, both recognized experts in DNA damage, senescence, inflammation and aging and with a strong track record in mentoring young investigators. The Research Development Core B (RCD) is co-directed by Drs. Paul Robbins (UMN) and Doug Mashek, who directs a UMN graduate program and is working on the novel role of lipid droplets in regulating DNA repair and senescence. The DNA Damage and Epigenetic Changes Core C is co-directed by Drs. Natalia Tretyakova and Peter Villalta, providing quantitative and reproducible mass spectroscopy approaches for accurately measuring oxidative DNA lesions and methods for measuring DNA methylation changes that occur following DNA damage. The DNA Damage Signaling and Repair Core D is co- directed by Drs. Revelo and Elizabeth Schmidt, providing CyTOF single cell analysis of DNA damage, DDR signaling and senescence at the protein level in single cells and measuring DNA repair capacity in primary cells. Finally, the Models of Genome Instability and Aging Core E, directed by Drs. Laura Niedernhofer and Christina Camell, will provide mouse and human cells and tissues deficient in different key DNA repair proteins as well as access to mouse models of accelerated DNA damage, senescence and aging for drug testing.