Pharmacological NRF2 activation as a strategy for protecting mitochondrial DNA at University of Dundee on FindAPhD.com

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Prof A Dinkova-Kostova, Dr B Rumsey No more applications being accepted Funded PhD Project (UK Students Only)

About the Project

Maintaining intracellular homeostasis and mitochondrial health in a changing environment is essential for cell survival. The nuclear factor-erythroid 2 p45-related factor 2 (NRF2, gene name NFE2L2) allows adaptation and survival under various conditions of stress. Activation of NRF2 results in upregulation of networks of proteins that protect against the consequences of proteotoxic, oxidative and inflammatory stress; conversely, the ability to upregulate NRF2 is compromised in many pathological conditions, and NRF2 is now considered a drug target.

NRF2 plays an important role in the control of cellular bioenergetics and mitochondrial health. Pharmacological activation of NRF2 protects against excess production of reactive oxygen species (ROS) by mitochondria and NADPH oxidase, and inhibits inflammation. Excess production of ROS during oxidative stress and inflammation can oxidize mitochondrial DNA (mtDNA), which then exits the mitochondrion, triggering inflammation. The overall goal of this project is to test the hypothesis that pharmacological activation of NRF2 protects mtDNA against damage and the ensuing inflammation. First, we will determine the effect of pharmacological NRF2 activation on the presence of mtDNA in the cytosol, following challenge with pro-inflammatory stimuli (lipopolysaccharide) or redox cycling agents (paraquat or its mitochondria-targeted derivative, mito-paraquat). Second, we will employ machine learning approaches for identification and design of NRF2 activators that protect mtDNA and mitochondrial health. Third, we will characterize the mechanism by which NRF2 activation protects mtDNA.

Together, the results from this project will establish whether pharmacological activation of NRF2 is an efficient strategy for protecting mtDNA against damage, and elucidate the underlying mechanism(s). Furthermore, it may lead to identification of new compounds for subsequent development as therapeutic agents for the maintenance of mitochondrial health.

Apply
Please send your CV and two references to [Email Address Removed] by 1st February 2019.

Funding Notes

This is a BBSRC-funded industrial CASE PhD studentship between UoD and GlaxoSmithKline (GSK). CASE studentships (formerly known as 'Collaborative Awards in Science and Engineering') are collaborative training grants that provide students with a first-rate challenging research training experience, allowing top quality bioscience graduates to undertake research, leading to a PhD, within the context of a mutually beneficial research collaboration between academic and partner organisations. The student will have the opportunity to spend part of their time with the partner company, GSK for a placement period of a minimum of 3 months, and up to a maximum of 18 months.

References

References:
Hayes, J. D. & Dinkova-Kostova, A. T. (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39, 199-218.
Kovac, S. et al. (2014) Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochim Biophys Acta 1850, 794-801.
Mills, E. L. et al. (2018) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113-117.
Zhong, Z. et al. (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560, 198-203.
Zhong, Z. et al. (2016) NF-kappaB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell 164, 896-910.

Where will I study?

University of Dundee

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Pharmacological NRF2 activation as a strategy for protecting mitochondrial DNA

University of Dundee School of Medicine