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Direct characterisation of TRPC channel dynamics triggered by drug-like modulators using high-speed atomic force microscopy

Faculty of Engineering and Physical Sciences

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Dr G Heath Applications accepted all year round Competition Funded PhD Project (European/UK Students Only)

About the Project

The rapid expansion in the structural understanding of membrane proteins through recent progress in electron microscopy and X-ray crystallography is leading to an ever greater need for techniques which provide high temporal resolution dynamics. High-Speed Atomic Force Microscopy (HS-AFM) gives unprecedented real-space and real-time visualisation of biological molecules (100 ms temporal resolution). This offers the unique capability to directly study how protein function can be modulated by various small molecules and stimuli to inform the pursuit of therapeutics.

Transient receptor potential canonical (TRPC) 1/4/5 channels are found in many cell types including the nervous and cardiovascular systems, where they form nonselective cationic channels with high calcium permeability. Structural and mechanical knowledge of these channels is rapidly evolving, suggesting TRPC1/4/5 assemblies play crucial roles in human physiology and pathology, and consequently are potential drug targets for renal failure, anxiety, cancer, pain, and cardiac remodeling.

Our goal is to study the dynamic structural changes in TRPC1/4/5 assemblies reconstituted into near-native membranes as a function of modulators by high speed AFM. The mechanisms we aim to uncover will not only be applicable to TRPC but also to all other TRP and heteromeric ion channels for which structural information is scarce and will therefore have important implications for general channel physiology and pharmacology. This highly interdisciplinary research will be performed in the School of Physics and Astronomy at the University of Leeds in collaboration with researchers in Leeds Institute of Cardiovascular and Metabolic Medicine.

Funding Notes

Funding Eligibility - UK/EU – Leeds Doctoral Scholarship Award, School of Physics & Astronomy paying Academic Fees and Maintenance matching EPSRC rate of £15,009 per year for 3 years. Alumni Bursary is available to previous University of Leeds graduates offering 10% discount on Academic Fees.

Funding Eligibility - International Students – China Scholarship Council-University of Leeds Scholarship Award, School of Physics & Astronomy Fee Only Scholarship paying Academic Fees for 3 years, Commonwealth Scholarship and Commonwealth Split Site Scholarships.  Alumni Bursary is available to previous University of Leeds graduates offering 10% discount on Academic Fees.

Self-funded students are also very welcome to apply
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