About the Project
Ghrelin is an endogenous growth hormone secretagogue and neuropeptide that enhances food intake and appetite, and which signals via the GHSR1 receptor. Patients with ALS have markedly reduced circulating levels of ghrelin, despite having a lower body mass index than age-matched controls1. This suggests that impaired ghrelin signalling may contribute to disease progression.
In models of neurodegeneration ghrelin protects against mitochondrial dysfunction and degeneration2, reduces neuroinflammation3, and crucially for this study, protects against motor neuron cell death in vitro4. As cytotoxicity, neuroinflammation and impaired redox balance are all implicated in ALS, a thorough evaluation of the effects of GHSR1 agonists is now essential.
This project aims to investigate the effects of GHSR1 agonists on motor neurons. Specific objectives are:
1. To identify whether ghrelin modulates the production of reactive oxygen
species in motor neurons and whether they modulate expression and activity of antioxidant defences
2. To define the effects of ghrelin on motor neuron mitochondrial dynamics and function
3. To understand whether ghrelin can modulate the physiological properties of
motor neurons
This project will be jointly hosted at the Universities of St Andrews (cell and molecular biology) and Dundee (electrophysiology). The student will enter into established research teams who have published together on other neurodegenerative conditions. However, the student will be exploring a novel area of collaboration between the two labs.
Funding Notes
This project is offered as part of the SPRINT-MND/MS PhD Programme. You should apply by downloading and completing the application form (select Apply Online for the link), quoting the reference SPRINT code on the projects(s) you are interested in applying for. Once you have fully completed the application form please email it to [Email Address Removed]. Please contact your referees and arrange for them to send your references directly to the 'sprint-phd' email address, with your full name in the subject line.
If you have an enquiry about the programme please email [Email Address Removed]
References
1. Ngo S.T., Steyn F.J., Huang L., Mantovani S., Pfluger C.M.M., Woodruff T.M., O’Sullivan J.D., Henderson R.D., McCombe P.A. Altered expression of metabolic proteins and adipokines in patients with amyotrophic lateral sclerosis. J. Neurol. Sci. 2015;357:22–27.
2. Yu J., Xu H., Shen X., Jiang H. Ghrelin protects MES23.5 cells against rotenone via inhibiting mitochondrial dysfunction and apoptosis. Neuropeptides. 2016;56:69–74.
3. Unger M.M., Oertel W.H., Tackenberg B. Cerebrospinal fluid
concentrations of ghrelin in patients with multiple sclerosis. Neuro Endocrinol. Lett. 2013;34:14–17
4. Lim E., Lee S., Li E., Kim Y., Park S. Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β pathways. Exp. Neurol. 2011;230:114–122.
5. Doherty G. H., Beccano-Kelly D., Yan S. D., Gunn-Moore F. J., Harvey J. Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β. Neurobiol. Aging 2013:34, 226–237.
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