Red Cell Physical Properties in Health and Disease

The red blood cell membrane has remarkable physical properties, which are major determinants of blood flow, particularly in the microcirculation. For example, blood flow through small capillaries requires fine-tuning of membrane shape and elasticity. Many diseases are associated with impaired microvascular function which has been attributed to changes in the physical properties of the red cell membrane arising from the oxidative stress to which the cell is subjected. More recently, strong evidence has begun to appear that the RBC also plays an active role in controlling microcirculation through the release of chemical signalling agents. For example, release of ATP from red cells (which stimulates the dilation of blood vessels), is stimulated by mechanical deformation of the red cell membrane, and is compromised in diabetes. Such evidence makes clear that the physical properties of red, and other, cells play important roles in controlling biological function.

In this project we will develop new experimental methodologies to analyse quantitatively the physical properties of the red cell membrane on the basis of novel computational models of membrane dynamics. We will investigate, experimentally and theoretically, the role different lipid species play in setting membrane elasticity and membrane electrical properties, how different lipid species are organised in larger formations called lipid microdomains, and how these processes are affected by oxidative stress. With the help of these insights, we will develop new computational models of the cell as a whole which, in combination with novel experimental methodologies, will enable us to accurately measure the elastic constants of the red cell. We will use these novel methodologies in the the final part of the project to investigate how the red cell membrane physical properties (elasticity, electrical potentials) affect biochemical sugnalling originating from the red cell. In these studies, we shall seek to establish whether membrane deformation, mechanical properties and/or oxidative stress affect production and release of two signalling agents, ATP (a known vesodilator) and sphingosine-1-phosphate (a signalling sphingolipid and a regulator of the vascular and immune systems).

We expect that these studies will contribute to the understanding of the origin of membrane elasticity in red cells, how it is changed in disease an how it can affect biochemical signalling pathways, as well as suggest new therapeutic targets and approaches.

This project is expected to lead to a number of academic and societal impacts. Although this is not a clinical study, we expect impacts to arise in the area of healthcare and future healthcare technologies. There is overwhelming experimental evidence that oxidative stress contributes critically to the development and detrimental effects of many diseases, posing an urgent and currently unfilled need for accessible methods to monitor damage caused by oxidative stress and responses to therapeutic measures. We propose that the red cell could be used as a reporter for disease and its progression if our hypothesis that RBC physical properties correlate with clinical markers for disease is confirmed. This would offer opportunities for development of novel and unconventional technologies for assessing the effect of oxidative stress and new monitoring tools for disease progression based on quick single cell measurements. Such an approach will be of relevance to the pharmaceutical industry as well, as it will provide a novel screening mechanism to establish possible antiglycation/antioxidative properties of new drugs which may lead to a wider spectrum of applications for existing formulations.

This is a highly interdisciplinary project and will contribute towards developing and strengthening the role biophysics plays in addressing fundamental disease-related problems. Biophysics is currently one of the most dynamic areas of science and has the potential to contribute not only to the understanding of normal physiology and biological function, but also significantly add to the understanding of impaired function in disease. In the process, we will also train highly skilled interdisciplinary researchers whose future work is likely to focus on the boundary between physics, biology and medicine, either in academia or outside it, and thus contribute to the wider society.

We would also like to engage in increasing public understanding of inter- and multidisciplinary science, in particular biophysics. This will give us the opportunity to raise awareness specifically of the contribution of physics to biology and medicine. So far, physics has largely been perceived as contributing to biology and healthcare through instrument development, but our aim will be to highlight the numerous new original approaches biophysics can offer in unravelling biological function in both health and disease.