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Glutaredoxin-1 As A Therapeutic Target In Neurodegenerative Inflammation

Miller, Olga Gorelenkova

Abstract Details

2017, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
Parkinson's disease (PD) is a debilitating movement disorder. Degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta is the main feature of PD. PD primarily affects the elderly, and it is incurable. The main treatment for PD is Levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine), a brain-permeable precursor of dopamine, alleviates disease symptoms by replenishing the neurotransmitter lost due to neuronal degeneration. However, L-DOPA does not block disease progression. PD is a social as well as an economic burden. Currently, over 1 million Americans are suffering from PD, and medical care for PD patients costs an estimated $23 billion per year in the US. Therefore, developing better treatments for PD is paramount. Inflammation has been implicated in PD etiology. Increased concentrations of inflammatory cytokines have been detected in the midbrain of PD animal models and PD patients. Anti-inflammatory agents have been found to decrease DA neuronal loss in animal models of PD. Moreover, increased use of non- steroidal anti-inflammatories (NSAIDs) has been correlated with a decrease in the probability of developing PD in humans. Therefore, anti-inflammatory agents represent an attractive avenue for PD treatment. Glutaredoxin-1 (Grx1) is a ubiquitously expressed oxidoreductase enzyme that specifically catalyzes reduction of glutathionyl mixed disulfides. Grx1 has been implicated as a positive regulator of inflammation in a variety of inflammation models. Moreover, Grx1 is upregulated by various inflammatory stimuli in distinct cell types, thereby potentially creating a feed-forward loop of inflammatory propagation. Grx1 silencing inhibits pro-inflammatory cytokine release in cell culture and animal models of inflammatory disease. It is therefore plausible that Grx1 contributes importantly to the inflammatory response observed in PD, and could represent a therapeutic target. Research presented in this thesis focuses on examining Grx1 as an inflammatory mediator and a target for anti-inflammatory therapy. The first part of this thesis research documents the pro-inflammatory role of Grx1 in microglia, resident macrophages of the central nervous system; and discovers a deleterious role for Grx1 upregulation in PD. The second part of this thesis focuses on characterizing a novel Grx1 inhibitor, CWR-J02, and its anti-inflammatory properties.
John Mieyal, PhD (Advisor)
Amy Wilson-Delfosse, PhD (Committee Chair)
Gary Landreth, PhD (Committee Member)
George Dubyak, PhD (Committee Member)
Richard Zigmond, PhD (Committee Member)
279 p.

Recommended Citations

Citations

  • Miller, O. G. (2017). Glutaredoxin-1 As A Therapeutic Target In Neurodegenerative Inflammation [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1493307283210551

    APA Style (7th edition)

  • Miller, Olga. Glutaredoxin-1 As A Therapeutic Target In Neurodegenerative Inflammation. 2017. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1493307283210551.

    MLA Style (8th edition)

  • Miller, Olga. "Glutaredoxin-1 As A Therapeutic Target In Neurodegenerative Inflammation." Doctoral dissertation, Case Western Reserve University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1493307283210551

    Chicago Manual of Style (17th edition)