LICAMM Computer simulations of force detection in cardiovascular disease

Summary

Mechanical forces are required for many functions in biology e.g., forces that are created by the heart play a vital role in the cardiovascular system as they regulate vascular functions such as endothelial cell alignment to blood flow, red blood cell volume regulation and cardiac remodelling. For this reason, mechanical forces are important in several cardiovascular diseases including heart failure, hypertension, and atherosclerosis. However, how force is sensed in the cardiovascular health and disease is currently an important but unresolved question in biology. This project will use state-of-the-art computational methodologies to answer this question. This new knowledge is critical, and it will enable new and improved therapeutic approaches for cardiovascular diseases.

The recent identification of Piezo1 as sensors of mechanical force makes it a key player in cardiovascular health and disease. Piezo1 a critical mechanical sensor in endothelial cells, red blood cells, cardiac fibroblasts, and other cell types. Piezo1 is a large ion channel, and its function is to permeate ions in response to mechanical stimuli. Mutations that result in the malfunction of Piezo1 have been implicated in a number of human cardiovascular diseases including dehydrated hereditary stomatocytosis and congenital lymphatic dysplasia. Genetic links to other diseases such as varicose veins and hypertension has also been identified. Therefore, understanding the mechanisms by which Piezo1 is able to sense and respond to mechanical force is critical as it can lead to molecular understanding of cardiovascular diseases.

In this project the student will use molecular dynamics simulations and molecular modelling to determine how disease-causing mutations may alter Piezo1 activation. Molecular dynamics simulations is a well-established technique that enables us to follow the dynamics of membrane proteins in a membrane environment. Therefore, they can provide detailed molecular and dynamic understanding of the function of membrane proteins. The specific Objective are:

1. Build computer models of wild-type human Piezo1 channel activation by mechanical forces.

2. Determine the effects on the models of human disease mutations.

3. Determine if cholesterol concentration alters the effects of the mutations.

This project will enable the student to develop cutting-edge computational skills that may dramatically improve the possibility to predict disease outcomes based on genetic data. The student will be a part of a multidisciplinary team that already studies Piezo1 and has extensive experience on how to study Piezo1 channel using both advanced computational and lab-based approaches. This opportunity would suit a student with a biology, biochemistry, chemistry or physics background, or a combination of these. Training in molecular simulations or associated computational methods will be provided and therefore no prior experience is needed.

References

1. Chong, J., D. De Vecchis, A.J. Hyman, O. V Povstyan, M.J. Ludlow, J. Shi, D.J. Beech, and A.C. Kalli. 2021. Modeling of full-length Piezo1 suggests importance of the proximal N-terminus for dome structure. Biophys. J. 120: 1343–1356.
2. De Vecchis, D., D.J. Beech, and A.C. Kalli. 2021. Molecular dynamics simulations of Piezo1 channel opening by increases in membrane tension. Biophys. J. 120: 1510–1521.
3. Shi, J., A.J. Hyman, D. De Vecchis, J. Chong, L. Lichtenstein, T.S. Futers, M. Rouahi, A.N. Salvayre, N. Auge, A.C. Kalli, and D.J. Beech. 2020. Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels. Cell Rep. 33.
4. Li, J., B. Hou, S. Tumova, K. Muraki, A. Bruns, M.J. Ludlow, A. Sedo, A.J. Hyman, L. McKeown, R.S. Young, N.Y. Yuldasheva, Y. Majeed, L.A. Wilson, B. Rode, M.A. Bailey, H.R. Kim, Z. Fu, D.A.L. Carter, J. Bilton, H. Imrie, P. Ajuh, T.N. Dear, R.M. Cubbon, M.T. Kearney, K.R. Prasad, P.C. Evans, J.F.X. Ainscough, and D.J. Beech. 2014. Piezo1 integration of vascular architecture with physiological force. Nature. 515: 279–282.
5. Beech, D.J., and A.C. Kalli. 2019. Force Sensing by Piezo Channels in Cardiovascular Health and Disease. Arterioscler. Thromb. Vasc. Biol. 39: 2228–2239.

A degree in biological sciences, dentistry, medicine, midwifery, nursing, psychology or a good honours degree in a subject relevant to the research topic. A Masters degree in a relevant subject is desirable but not essential.

Applicants whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The minimum requirements for this programme in IELTS and TOEFL tests are: • British Council IELTS - score of 7.0 overall, with no element less than 6.5 • TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.