Role of IFI 16 in Cellular Senescence and Aging

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This proposal addresses Research Objective # 14; Understand Healthy Aging Processes. Cellular senescence or replicative senescence refers to the irreversible cell cycle arrest displayed by cells that have exhausted their replicative potential. Based on several studies, it is evident that senescent cells accumulate with age in human tissues and organs where cell turnover is common. These studies also raise the possibility that the slow growth and metabolism of senescent cells can lead to tissue failure and degenerative diseases during aging. Additionally, bypassing of replicative senescence could lead to aging-related cancers. Therefore, identification of senescence genes and a clear understanding of their role in senescence pathways are needed to diagnose and treat aging-related diseases effectively. Although genetic studies have indicated that the long arm of human chromosome 1 harbors genes regulating senescence, the identities of these genes remain unknown. Our recent experiments indicated that levels of IFI 16 protein, encoded by the gene IFI 16 (location 1q22) from the 200-gene family, are higher in older populations of human fibroblasts than young fibroblasts. Based on this observation and others, we hypothesize that the gene IFI 16 is a candidate for regulating replicative senescence in culture and aging in vivo. Specific aim #1 : To investigate the role of IFI 16 in replicative senescence. We propose to: (i) study the kinetics of IFI 16 induction in human fibroblasts when they approach replicative senescence in culture; (ii) measure the induction of replicative senescence in human fibroblasts in which IFI 16 levels are decreased using an antisense approach; and (iii) measure the induction of senescence in human cell lines from the complementation group C (defective in chromosome 1) to see whether inducible (tetracycline-repressible) expression of IFI 16 in cells of these lines reverses the immortal phenotype. Specific aim #2: To elucidate the molecular mechanism(s) activating the expression of IFI 16 gene during the induction of replicative senescence in human fibroblasts. We will test whether the transcription factor KLF6, a candidate for tumor suppressor, activates transcription of the IFI 16 gene. Siqnificance: The proposed studies will test whether the gene IFI 16 is a candidate for regulating the replicative senescence. Importantly these studies will provide the preliminary data and evidence that we can perform these techniques for an R01 application.