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  MScR - Preserving t-tubule function in adult cardiac myocytes in short-term culture


   School of Physiology, Pharmacology & Neuroscience

  ,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Invaginations of the sarcolemma of adult cardiac myocytes known as transverse (or t-) tubules account for up to 65% of the total sarcolemma surface and play a key role in excitation-contraction (EC) coupling and cell signalling (Hong & Shaw, 2017). Disruption to the t-tubule network in cardiac disease contributes to dysfunction and arrhythmia susceptibility (Orchard et al., 2013; Bryant et al., 2015). The mechanisms underlying the genesis and maintenance of t-tubules are not fully understood but the major proteins involved include caveolin-3, bridging-integrator-1 (Bin-1, also known as amphiphysin-2), and dysferlin (Hong & Shaw, 2017). The t-tubules of adult isolated cardiac myocytes are lost progressively with time culture, making short-term cell culture a useful experimental approach for the investigation of t-tubule genesis and maintenance (Mitcheson et al., 1996; Louch et al., 2004; Pavlovic et al., 2010; Hong & Shaw, 2017).

A recent report suggests that loss of t-tubules from adult ventricular myocytes in culture was associated with the mis-localization of JPH2 and that the t-tubule network could be stabilised by the overexpression of JPH2 using an adenoviral vector (Poulet et al., 2021). Transfection of cultured cells with Bin-1 has previously been shown to cause t-tubule biogenesis, although it is not known whether overexpression of Bin-1 would rescue t-tubules in adult cardiac myocytes in culture (De La Mata et al., 2019).

This project aims to investigate whether t-tubule structure and function can be preserved in adult ventricular myocytes in culture by the overexpression of JPH2 or Bin-1. The project will involve cloning and molecular biological techniques to produce the constructs, the isolation and culture of ventricular myocytes from adult hearts, fluorescence imaging and whole cell patch clamp recording to examine ion currents in intact and detubulated myocytes.

How to apply:

MSc by Research (MScR) is a 1-year research degree that provides an intensive lab-based training and a preparation for PhD study. You will carry out your studies as part of your research group – like a PhD student does. Towards the end of the year, you write up a thesis on your research and are examined on this. This degree suits students wanting to gain maximum research experience in preparation for PhD applications.

We are keen to recruit a diverse range of students and to ensure our research is open to all. We particularly welcome applications from groups traditionally under-represented in life sciences research. Please check the University webpages for the current tuition fee information. Most MScR projects also require a bench fee. This varies depending on the research and your project supervisor can tell you the bench fee for the project.

Please follow the link below and apply to the Faculty of Life Sciences, School of Physiology, Pharmacology and Neuroscience, selecting the programme "Physiology, Pharmacology and Neuroscience (MSc by Research)".

PhD Physiology, Pharmacology and Neuroscience | Study at Bristol | University of Bristol


Biological Sciences (4) Medicine (26)

Funding Notes

This project is available to UK and international students who wish to self-fund their MScR or who have access to their own funding.
Please contact Prof James directly for information about the project and how to apply.

References

Bryant SM, Kong CHT, Watson J, Cannell MB, James AF & Orchard CH. (2015). Altered distribution of ICa impairs Ca release at the t-tubules of ventricular myocytes from failing hearts. J Mol Cell Cardiol 86, 23-31. doi: 10.1016/j.yjmcc.2015.06.012
De La Mata A, Tajada S, O'Dwyer S, Matsumoto C, Dixon RE, Hariharan N, Moreno CM & Santana LF. (2019). BIN1 Induces the Formation of T-Tubules and Adult-Like Ca2+ Release Units in Developing Cardiomyocytes. Stem Cells 37, 54-64. doi: 10.1002/stem.2927
Hong T & Shaw RM. (2017). Cardiac T-Tubule Microanatomy and Function. Physiol Rev 97, 227-252. doi: 10.1152/physrev.00037.2015
Louch WE, Bito V, Heinzel FR, Macianskiene R, Vanhaecke J, Flameng W, Mubagwa K & Sipido KR. (2004). Reduced synchrony of Ca2+ release with loss of T-tubules—a comparison to Ca2+ release in human failing cardiomyocytes. Cardiovasc Res 62, 63-73. doi: 10.1016/j.cardiores.2003.12.031
Mitcheson JS, Hancox JC & Levi AJ. (1996). Action potentials, ion channel currents and transverse tubule density in adult rabbit ventricular myocytes maintained for 6 days in culture. Pflug Arch 431, 814-827. doi: 10.1007/s004240050073
Orchard CH, Bryant SM & James AF. (2013). Do t-tubules play a role in arrhythmogenesis in cardiac ventricular myocytes? J Physiol (Lond) 591, 4141-4147. doi: 10.1113/jphysiol.2013.254540
Pavlovic D, McLatchie LM & Shattock MJ. (2010). The rate of loss of T-tubules in cultured adult ventricular myocytes is species dependent. Exp Physiol 95, 518-527. doi: 10.1113/expphysiol.2009.052126
Poulet C, Sanchez-Alonso J, Swiatlowska P, et al. (2021). Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes. Cardiovasc Res 117, 149-161. doi: 10.1093/cvr/cvaa03

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