Why muscles weaken and immunity fails: Investigating the role of calmodulin

About this opportunity

Background. Calcium signals are essential for processes such as muscle contraction, immune activation, and brain function. They are controlled by calcium channels that regulate calcium entry into cells. Mutations in these channels cause channelopathies, leading to diverse diseases. Recently, severe mutations in Orai1 and STIM1 have been linked to muscular hypotonia and immunodeficiency. Many occur where these channels interact with calmodulin, a universal calcium sensor. Although calmodulin is crucial for calcium regulation, its role in Orai1 and STIM1 control remains poorly understood, leaving a major knowledge gap. This project will investigate how calmodulin interacts with these channels, and how mutations disrupt this regulation, leading to disease. By linking molecular defects to muscle and immune dysfunction, we aim to uncover the mechanisms behind these conditions. Insights gained could not only explain rare disorders but also guide therapeutic strategies and advance understanding of calcium signalling in health and disease.

Hypothesis and aims. We hypothesise that mutations in Orai1 and STIM1 disrupt normal calmodulin regulation of calcium channels, leading to abnormal signalling that underlies muscular hypotonia and immunodeficiency. The specific aims of the project are to:

1. Characterise calmodulin binding to Orai1 and STIM1, in both healthy and disease-associated forms.
2. Determine how calmodulin regulates calcium channel activity in living cells.
3. Resolve structural features of calmodulin-channel complexes, identifying conformational changes caused by mutations.
4. Link molecular changes to cellular consequences, showing how defective signalling contributes to muscle and immune dysfunction.

Research plan. This PhD will combine biochemistry, structural biology, cell physiology, and electrophysiology to develop a detailed understanding of calmodulin regulation in channelopathies.

• Molecular biology and protein biochemistry: Mutant and wild-type versions of Orai1 and STIM1 will be engineered. Protein binding assays will be used to quantitatively map calmodulin interaction sites.
• Functional studies: Live-cell calcium imaging and patch-clamp electrophysiology will reveal how calmodulin influences channel behaviour in real time.
• Structural biology: X-ray crystallography will be applied to visualise calmodulin-channel complexes at high resolution.
• Cell-based studies: We will link molecular defects to physiological outcomes using muscle and immune cells.

By integrating these approaches, the student will generate both mechanistic insights and disease-relevant connections.

Outcomes. This project will define how calmodulin regulates Orai1 and STIM1, showing how mutations disrupt calcium signalling and cause hypotonia and immunodeficiency. By linking molecular defects to cellular effects, it will close a key knowledge gap in calcium channelopathies and highlight therapeutic targets. Insights will also advance understanding of calcium signalling in cardiovascular, nervous and immune systems.

Training and development opportunities. This PhD project offers exceptional training across disciplines, providing the successful candidate with a highly versatile skill set.

• Molecular cloning, mutagenesis, and protein engineering.
• Protein purification and binding studies.
• Advanced microscopy (confocal and super-resolution imaging).
• Electrophysiology (patch-clamp techniques).
• Structural biology approaches for protein complexes.
• Cell culture and live-cell functional assays.
• Transferable skills (critical thinking, experimental design, data analysis, scientific writing, and oral presentation).

Who is this for?

We welcome applications from motivated and ambitious students with a strong interest in understanding how molecular mechanisms underlie human disease. Applicants should hold (or expect to obtain) at least a 2:1 undergraduate degree (or equivalent) in a life science or health-related subject (e.g. biochemistry, molecular biology, physiology, pharmacology).

This PhD will particularly appeal to candidates aiming for careers in biomedical research, biotechnology or translational science.

Additional costs

We understand that budgeting for your time at university is important, and we want to make sure you understand any costs that are not covered by your tuition fee. This could include buying a laptop, books, or stationery.

Find out more about the additional study costs that may apply to this project, as well as general student living costs.

Funding your PhD

We are looking for a self-funded student who has secured funding from an independent source. There is no financial support available from Liverpool for this study.

The successful applicant will be expected to have funding in place for the tuition fees (https://www.liverpool.ac.uk/study/fees-and-funding/tuition-fees/postgraduate-research), consumables/bench fee (£12,000 per annum) and living expenses during their stay in Liverpool.

If you're a UK national, or have settled status in the UK, you may be eligible to apply for a Postgraduate Doctoral Loan worth up to £30,301 to help with course fees and living costs.

There’s also a variety of alternative sources of funding. These include funded research opportunities and financial support from UK research councils, charities and trusts. Your supervisor may be able to help you secure funding.

Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.