Project 1 Outline: Mmm… Molecular Mechanisms of MRAP2: Investigating a Key Regulator of Appetite in the Brain
Supervisor(s)
Dr Javier Tello (School of Medicine) & Dr Paolo Annibale (School of Physics & Astronomy)
Project description
Obesity poses a major public health challenge, significantly raising the risk of heart disease, stroke, type 2 diabetes, and Alzheimer’s disease. In the UK, more than 28% of adults are currently classified as obese, with forecasts suggesting this number could rise to 26 million cases within the next 20 years.
The melanocortin 4 receptor (MC4R) plays a central role in processing hunger signals in the brain as its inactivation leads to severe obesity. Its function is closely tied to trafficking proteins, particularly Melanocortin Receptor Accessory Protein 2 (MRAP2), a key regulator of appetite and energy balance. While the underlying mechanisms remain poorly understood, emerging evidence suggests that MRAP2 modulates MC4R activity by guiding its localisation to specific subcellular compartments essential for initiating signal transduction (1, 2).
This project will test the hypothesis that MRAP2 is required for MC4R trafficking and effective signal transduction in neurons involved in the brain’s regulation of energy homeostasis.
To do this, we will employ cutting-edge single cell imaging and functional fluorescence microscopy. By using fluorescent ligands and fluorescence correlation spectroscopy, we will track MC4R dynamics in live neurons, assessing surface receptor expression over time in response to agonist stimulation with and without MRAP2 expression. In parallel, we will use GFP- and FRET-based cAMP sensors (G-Flamp or EPAC-cAMPs) to monitor real-time changes in intracellular cAMP, offering insights into MRAP’s role in MC4R-mediated signal transduction.
This interdisciplinary studentship offers a unique opportunity for hands-on training in molecular pharmacology, neurobiology, advanced imaging and single-cell analysis. Supervised by Dr Javier Tello (School of Medicine) and Dr Paolo Annibale (School of Physics & Astronomy), the project bridges expertise in neurobiology and biophysics. The student will gain valuable experience in neuronal culture, live-cell imaging and quantitative analysis, positioning them for future careers in biotechnology, pharmaceutical research, or further academic study at the PhD level.
Relevant References
- Brouwers, Bas, et al. “Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.” Cell reports12 (2021).
- Sohail, Iqra, et al. “MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor.” bioRxiv(2024): 2024-04.
Subject area(s) and keywords
Obesity, Appetite regulation, Neurobiology, Energy homeostasis, Melanocortin system, Real-time imaging, Fluorescence microscopy, Neurobiology and biophysics interface
Schools of Medicine and Physics and Astronomy, University of St Andrews
The successful applicant will join dynamic and well-established research laboratories within a highly collaborative and stimulating environment. Both the Schools of Medicine and Physics & Astronomy are located on a vibrant, interactive research campus at the forefront of cell signalling, bioimaging and molecular medicine research. This setting offers an exceptional opportunity to engage in cutting-edge research at the intersection of cell signalling, bioimaging and molecular medicine, with a strong emphasis on understanding the molecular mechanism of disease through the application of advanced imaging technologies.
The schools are committed to equal opportunities and values all applicants. The School of Medicine currently has Athena SWAN bronze accreditation and Physics and Astronomy has a SWAN Silver awards since 2017.
Further details and application process
This project has been awarded IBANS Research Bursary of £1000 for research expenses. If you are planning to apply for this project, first contact the supervisors, Dr Javier Tello ([email protected]) and Dr Paolo Annibale ([email protected]), to discuss eligibility and obtain approval. Once an agreement is reached, you can proceed to submit your formal application.