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EVALUATING THE ROLE OF NF-êB SUPPRESSION IN AMELIORATING MAMMALIAN DISEASE: AN EXAMINATION OF INFLAMMATORY BOWEL DISEASE AND DISEASES ASSOCIATED WITH AGING

Tilstra, Jeremy Scott (2009) EVALUATING THE ROLE OF NF-êB SUPPRESSION IN AMELIORATING MAMMALIAN DISEASE: AN EXAMINATION OF INFLAMMATORY BOWEL DISEASE AND DISEASES ASSOCIATED WITH AGING. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

NF-êB is a family of transcription factors that play a pivotal role in inflammation, cell proliferation, cell survival, and apoptosis in response to endogenous and exogenous stress stimuli. NF-êB is implicated in numerous chronic inflammatory and degenerative diseases. In this thesis, the consequences of NF-êB suppression on pathologies associated with inflammatory bowel disease (IBD) and age-associated degeneration are explored. To test the hypothesis that NF-êB plays a causal role in driving the degenerative changes associated with the diseases we evaluated the efficacy of a pharmacologic peptide IKK/NF-êB activation inhibitor in the IL-10-/- model of colitis and genetic depletion and pharmacologic inhibition of NF-êB in a mouse model of accelerated aging (Ercc1-/∆ mice). Pathologic and immunologic markers of IBD were reduced in the presence of systemic pharmacologic NF-êB suppression. Furthermore, this study provides evidence of the efficacy of the NBD inhibitory peptide in vitro and in vivo experiments, and importantly provided possible therapeutic avenues for the treatment of IBD. Like naturally aged mice, NF-êB is activated in Ercc1-/∆ mice compared to wild type littermates. Ercc1-/∆ mice haploinsufficient for the p65/RelA subunit of NF-êB had a modest delay in the onset of age-related symptoms. This was recapitulated in mice chronically treated with the peptide inhibitor of NF-êB, which exhibited a significant delay in overall aging score and improved histopathological alterations. These implicate NF-êB as a major driver of degenerative changes associated with aging and set a precedent for therapeutic intervention. As activated macrophages are mediators of inflammatory and age-associated degenerative changes, we futher evaluated the role of NF-êB suppression in this cell type. Macropahges and monocyte derived DC cells underwent programmed cell death (PCD) in the presence of pharmacologic NF-êB inhibition. Unlike previous studies which implicated TNFá signaling in this pathway, the mechanisms behind this PCD is induction is induction of ROS formation. This observed macrophage NF-êB induced PCD may be one of the mechanisms by which inflammatory and age-associated disease pathologies are reduced in response to NF-êB suppression.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Tilstra, Jeremy Scottjst8@pitt.eduJST8
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairRobbins, Paul Dprobb@pitt.eduPROBB
Committee MemberNiedernhofer, Laura Jniedernhoferl@upmc.edu
Committee MemberKane, Lawrence Plkane@pitt.eduLKANE
Committee MemberFinn, Olivera Jojfinn@pitt.eduOJFINN
Committee MemberRay, Prabirrayp@pitt.eduRAYP
Date: 28 August 2009
Date Type: Completion
Defense Date: 11 August 2009
Approval Date: 28 August 2009
Submission Date: 25 August 2009
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: aging diseases including osteoporosis; and cachexia are assoicated with NF-kB activity; diabetes; IKKbeta inhibition; neurodegeneration; NF-kB inhibition induces macrophage cell death; sacropenia
Other ID: http://etd.library.pitt.edu/ETD/available/etd-08252009-113759/, etd-08252009-113759
Date Deposited: 10 Nov 2011 20:01
Last Modified: 15 Nov 2016 13:49
URI: http://d-scholarship.pitt.edu/id/eprint/9255

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