Intercellular communication
Professor Nicholas Severs, Principal Investigator
Research activities of the unit centre on cell and membrane interactions in cardiovascular cell function, a theme that encompasses a series of complementary topics. One major focus of continuing interest is on gap junctions, the plasma membrane structures responsible for cell-to-cell communication and electrical coupling. These junctions play essential roles in the normal function of the heart and arteries, mediating spread of the wave of electrical excitation that stimulates synchronised contraction of the cardiac chambers, and contributing to co-ordination of function between cells of the arterial wall. Specific research aims are to determine: i) how the expression of, and interaction between, different connexin types (i.e. molecular variants of gap junction proteins) contribute to functional specialisation in specific subsets of cardiac myocytes and vascular cells; and ii) the nature and significance of alterations in the spatial and temporal expression of different connexins in development and disease.
One finding to emerge from this work is that alterations of gap junction organization and connexin expression are a consistent feature of human heart disease in which there is an arrhythmic tendency. These alterations may take the form of structural remodelling, involving disturbances in the distribution of gap junctions and/or alteration of the amount or type of connexin(s) expressed. Key areas of current work include investigation of the mechanisms that regulate this remodelling, and the development of cell models in which multiple connexins are co-expressed under the control of inducible promoters to mimic the patterns observed in different cardiovascular cell types in vivo. These models permit determination of the functional correlates of the distinctive patterns of connexin co-expression and molecular make-up of the gap junction channel in health and disease.
The work on gap junctions and connexins is set within the wider perspective of mechanisms of substructural integration of myocyte electromechanical function, in which the cytoskeleton, anchoring junctions, plasma membrane-matrix junctions and other plasma membrane proteins and channels, all participate. The contribution of interactions between these components to the cellular basis for cardiovascular dysfunction is being explored. Complementary projects focus on interplay between growth factors, connexins and lipoprotein receptors in the diseased arterial wall.
The research of the group has a strong foundation in modern cellular imaging techniques (freeze-fracture electron microscopy, ultrarapid freezing, immunocytochemistry and confocal microscopy) applied in combination with cellular and molecular, biochemical and physiological approaches.
PhD and MD students are accepted in the group when vacancies and funding permit. Only individuals of the highest potential and calibre are considered. The completion period for PhD students within the group is 2.9-3.1 years, and the average number of publications per student from their thesis research is 6 papers and 7.75 conference abstracts. Higher degree students regularly receive prizes for their work: recent examples include the 1st Prize Young Microscopist Competition (Confocal Microscopy category), Royal Microscopical Society (1996) to Shirley Stevenson, the Professor Guy Scadding Award for Outstanding PhD Thesis (1997) to Hung-I Yeh, the Rogers Prize for Advance in Medicine (1998) to Raffi R. Kaprielian, NASPE Young Investigator Award (Runner-Up) & European Society for Cardiology Prize for Cardiac Electrophysiology (2003) Riyaz A. Kaba. Other awards to the group include the Rector’s Award for Excellence (2000) to Stephen Rothery for exceptional practical skills, the Robert Feulgen Prize of the Society for Histochemistry (1992) jointly to Colin Green and Nicholas Severs, and Foreign Membership of the Polish Academy of Arts & Sciences (1996) and the Polish Academy of Sciences (2000) to Professor Severs.
