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TARGETING MITOPHAGY TO REDUCE CHEMOTHERAPY-INDUCED PAIN


School of Pharmacy

Applications accepted all year round Self-Funded PhD Students Only

About the Project

"Background
Chemotherapy-induced peripheral neuropathy (CIPN) is the most commonly reported side effect of chemotherapeutic drugs, affecting quality of life in many cancer patients. Currently there are no approved drugs to treat this form of chronic pain. Paclitaxel (PTX) is a chemotherapeutic drug originally isolated from Pacific Yew, Taxus brevifolia, and is now widely used against several of the most common cancer, such as breast, lung and ovarian cancer (1). There is growing evidence that mitochondrial dysfunction is induced by various chemotherapeutics drugs that are associated with neuropathy, including Paclitaxel.
Mitochondria are cellular organelles surrounded by a double membrane. The unchecked accumulation of ROS can damage mitochondria and other cellular components. Atypical mitochondria (swollen and vacuolated) have been observed in sensory neurons in a rodent model of Paclitaxel-induced neuropathy(4) and the accumulation of reactive oxygen species (ROS) at key levels of nociceptive signalling integration has been linked to the development of paclitaxel-induced pain (5).
Mitochondrial quality is maintained by a form of autophagy known as mitophagy. (6). Autophagy is a degradative mechanism essential for a correct cellular homeostasis. A primary aim of this proposal is therefore to investigate the relationship between mitophagy in the peripheral and central nervous system and Chemotherapy-Induced Peripheral Neuropathy (CIPN). The main hypothesis for this research is that the development and maintenance of CIPN, associated with mitochondrial dysfunction and subsequent accumulation of ROS, is a consequence of the impairment of mitophagy.

While clinical trials are currently testing whether the modulation of autophagy could improve chemotherapy efficacy, targeting autophagy to reduce CIPN has been poorly investigated. We will therefore investigate whether pharmacological manipulation of autophagy may affect the onset of CIPN. Our hypothesis (2) is that manipulation of autophagy will ameliorate the severity of CIPN.

Methods include:
• Behavioural test for mechanical and thermal allodynia and anxiety-related behaviour
• Intraperitoneal and Intrathecal injections
• Immunohistochemistry
• Western blotting
• Confocal laser microscopy
• Fluorescent microscopy
• RT-qPCR


In conclusion, this is an exciting program of research that has the potential to lead to a better understanding of the mechanism underlying CIPN. The findings of this research can therefore lead to better treatment of the adverse effects of anticancer therapies, improving the quality of life of cancer survivors.

Key words: Pain, chronic pain, autophagy, Mitophagy, Pain treatment




For further information, please contact me at [email protected] .ac.uk"

Funding Notes

Students with their own financial support are welcome to contact us any time. Information regarding the tuition fees for postgraduate research students can be found at the webpage linked below: View Website

References

"1. E. Gornstein, T. L. Schwarz, Neuropharmacology. 76, 175–183 (2014).
2. S. E. Weinberg, N. S. Chandel, Nat. Chem. Biol. 11, 9–15 (2015).
3. D. R. Green, Science. 305, 626–629 (2004).
4. S. J. L. Flatters, G. J. Bennett, Pain. 122, 245–257 (2006).
5. N. A. Duggett et al., Neuroscience. 333, 13–26 (2016).
6. D. A. Kubli, Å. B. Gustafsson, Circ. Res. 111, 1208–1221 (2012)."

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