Aging Effect on Genome Maintenance during Hepatocyte Regeneration
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PROJECT SUMMARYLiver is a vital organ with a unique capability to regenerate after injuries via a dual mechanism. This ability,however, is significantly compromised by aging. Most studies that investigate the aging effect on liverregeneration focus on the signaling pathways that drive the cell cycle reentry and growth of regeneratinghepatocytes. A missing but critical piece of the puzzle, as a recent study from my lab has shown, is themechanism that maintains the regenerative potential of hepatocytes by safeguarding them from replication-induced DNA damage. The key driver of this program is a stem and cancer cell-enriched protein, nucleostemin(NS). To date, it remains unclear whether the NS pathway plays a determinant role in the age-associateddecline of liver regeneration and how its expression and activity is regulated in the liver during the agingprocess. To solve the puzzle of how aging affects liver regeneration, there is a critical need to determine themechanism by which aging regulates NS function in the liver. My long-term goal is to determine how self-renewal programs contribute to the regeneration and homeostasis of adult tissues during the aging process.The objective of this proposal is to determine the role of NS in age-associated decline of liver regeneration andhow its expression is down-regulated in regenerating hepatocytes during the aging process. Our centralhypothesis states that age-related NS down-regulation via a C/EBPÎ±-controlled mechanism sets a threshold(determinant) level that limits the regenerative potential of the liver. This hypothesis is formulated based on: 1)NS is up-regulated on or before the cell cycle reentry of regenerating hepatocytes and serves an essential rolein protecting them from replicative DNA damage; 2) NS deletion compromises liver regeneration after injuries;3) the levels of NS and Ki67 are both down-regulated in aged livers under the resting and regeneratingconditions compared to young livers; 4) NS promoter contains cognate C/EBPÎ±-binding sites, and itstranscriptional activity is inhibited by C/EBPÎ±; and 5) C/EBPÎ± is known to inhibit the regeneration of agedlivers. To test our hypothesis, two specific aims will be pursued. Aim 1 will determine the role of NS in age-associated decline of liver regeneration. Aim 2 will determine the transcriptional mechanism that drives NSdown-regulation during liver aging. At the completion, we expect to have determined the importance of NS insetting a threshold level that caps the regenerative potential of aged livers, and the transcriptional program thatdrives the down-regulation of NS during the aging process. These outcomes will fill the need to understand themolecules that underpin the age-related decline of liver regeneration and the mechanisms that may precipitateor alleviate the effect of aging on liver regeneration. A successful completion of this proposal will thereforehave a direct impact on resolving the health issues caused by age-dependent decline of liver regeneration anda broad impact on advancing research on the aging effect on the regeneration of other adult tissues.