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(Unpublished)
Abstract
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/27841 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[img]](https://d-scholarship.pitt.edu/style/images/fileicons/application_pdf.png)
![[feed]](/images/feed-icon-32x32.png){kind=icon}