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A causal role of ATM- and NEMO-dependent NF-κB activation in DNA damage-induced senescence and aging

Zhao, Jing (2016) A causal role of ATM- and NEMO-dependent NF-κB activation in DNA damage-induced senescence and aging. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The accumulation of senescent cells induced by intracellular and extracellular stress contributes to multi-organ dysfunction and aging. Persistent DNA damage chronically accumulates with aging initiating a cellular stress response termed DNA damage response (DDR). Ataxia-telangiectasia mutated (ATM) kinase, a core component of DDR signaling, is involved in p53-p21 and p16-Rb senescent effector pathways, and is essential for senescence-associated secretory phenotype (SASP). In addition, ATM activates NEMO-dependent NF-κB pathway in response to genotoxic stress. However, the underlying molecular mechanisms through which DNA damage drives senescence and aging remain poorly characterized. Here we used the Ercc1-/Δ mouse model of a human progeria that spontaneously develops osteoporosis, disc degeneration, glomerulonephropathy and neurodegeneration, to address the causal link between DDR-dependent NF-κB activation, cellular senescence and aging. In the first part, we demonstrated that DDR signaling, concomitant with NF-κB, was highly activated in Ercc1-/Δ mice. A causal role of ATM in DNA damage-induced aging was demonstrated by genetic depletion of ATM in Ercc1-/Δ mice, which extended health span as well as alleviated aging-related pathology. Moreover, ATM haploinsufficiency showed significantly reduced NF-κB activation and SASP. In vitro assays support an activation of ATM- and NEMO-dependent canonical NF-κB activation in response to oxidative stress. In the second part, we developed novel small molecule inhibitors to disrupt the interaction between IKKβ and NEMO/IKKγ. We demonstrated that novel NBD mimetics, in particular SR12343 and SR12460, efficiently inhibited both TNF-α and LPS-induced NF-κB activation in vitro. Additionally, the chronic treatment with SR12343 and SR12460 reduced LPS-induced acute inflammation in lung and liver, and improved muscle pathology in mdx mice, a murine model of Duchenne muscular dystrophy. In the third part, we demonstrated that chronic treatment of Ercc1-/Δ mice with SR12343 significantly improved aging symptoms and prolonged healthspan, as well as reduced the level of cellular senescence. Furthermore, suppression of IKK/NF-κB attenuated lipodystrophy and associated impaired glucose tolerance by reducing cellular senescence in fat. Taken together, these results suggest that NF-κB activation promotes cellular senescence and aging through an ATM-dependent pathway in Ercc1-/Δ mice and the ATM-IKK-NF-κB pathway represents a key target for the development of novel approaches for healthy aging.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhao, Jingjiz72@pitt.eduJIZ72
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRobbins, Paul
Committee MemberNiedernhofer, Laura J.LNiedern@scripps.eduNIEDERNH
Committee MemberPiganelli, Jon D.jdp51@pitt.eduJDP51
Committee MemberKane, Lawrence P.lkane@pitt.eduLKANE0000-0001-5198-516X
Committee MemberDe Vallejo, Abbe N.andv26@pitt.eduANDV26
Date: 20 May 2016
Date Type: Publication
Defense Date: 4 December 2015
Approval Date: 20 May 2016
Submission Date: 26 April 2016
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 142
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: DNA damage, Cellular Senescence, Aging, NF-κB, Progeria and NBD peptide
Date Deposited: 20 May 2016 15:22
Last Modified: 20 May 2017 05:15


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