Link between ATP supply and consumption in the maintenance of the shape of the red blood cell in normal and disease states

Summary

The link between the main energy supply (ATP from glycolysis) and its consumption by the cytoskeleton will be studied by using nuclear magnetic resonance (NMR) spectroscopy, computer simulation of metabolism, and differential interference contrast light microscopy.  

Supervisor(s)

Professor Philip Kuchel

Research Location

School of Molecular Bioscience

Program Type

Masters/PHD

Synopsis

Aims: The recent completion of a complex kinetic model of the metabolism of the human erythrocyte (red blood cell; RBC) paves the way for higher-level versions that relate to many cellular responses. The RBC’s ‘metabolic machine’ consists of the interconnected ‘modules’ of glycolysis, the pentose phosphate pathway, glutathione turnover, and the purine nucleoside salvage cycle, plus selective membrane transport proteins. It is often stated that the ‘purpose’ of RBCs is to deliver oxygen from the lungs to the tissues, but RBCs perform many other transport and metabolic reactions that support the operation of the whole body. The cell-physiological actions and properties of this small and simple cell are likely to be a subset of the features of complex cells like hepatocytes, myocytes and neurons. In this project, you will address a fundamental question that will deepen insight into the operation of the RBC, and in the process provide concepts and experimental tools that will be valuable for understanding how other types of cells ‘work’ at the molecular level. What is the cytoskeletal rate of ATP consumption? This question has not been solved because of a paucity of experimental approaches to the study ATP turnover in any living cell. The RBC has a simple cytoskeleton composed of ~500,000 copies of the main structural element, alpha- and beta-spectrin (Mr ~220,000). The geodetic-like structure underpins the phospholipid bilayer, and provides its tensile strength; it is also phosphorylated. Thus, what fraction of the total turnover of ATP involves the phosphorylation and dephosphorylation cycle of spectrin?

Additional Information

Other Information: In the project you will join the vigorous intellectual environment of a modern well-funded funded NMR lab; you will carry out your own project under my supervision with day-to-day help from other students and post-docs and increasingly you will gain your independence. You will also participate in a weekly lab meeting (1 h) where your experimental results (and any theory you may have worked on), and interpretations, are discussed along with those of other PhD students and post-docs in the group. The aim will be to make you conversant with modern NMR spectroscopy over the duration of your candidature and to this end you will engage in a weekly tutorial-workshop discussion centred on a modern NMR book. You will be taught the basic methods of writing Mathematica computer programs and explore your own NMR spectroscopy and metabolic simulations along with the large scale model of RBC metabolism using the book by Mulquiney and Kuchel for instructions. You will learn the biochemical and haematological methods needed to prepare RBCs and carry out experiments on metabolism and membrane transport processes. 

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Keywords

Haematological diseases associated with erythrocyte shape such as sickle cell disease, malaria, poikilocytosis, elliptocytosis and spherocytosis., NMR spectroscopy of cells, fast membrane transport, isotopomer analysis, computer modeling of metabolism, physical biochemistry, DIC microscopy, biomathematics., Cell biology, Human body

Opportunity ID

The opportunity ID for this research opportunity is: 37