Faculty of Biological Sciences

Dr Sarah Calaghan

BSc, PhD 1991, Leeds.
Associate Professor in Cardiac Physiology
School of Biomedical Sciences

Background: BSc, PhD (Leeds). Postdoctoral Research, Dept of Biochemistry & Molecular Biology, Dept of Physiology, University of Leeds. British Heart Foundation Research Fellow (2000-2003), School of Biomedical Sciences University Research Fellow (2006-), Institute of Membrane and Systems Biology

Contact:  Garstang 7.52d, +44(0) 113 34 34309, email address for  

Research Interests

Control of signalling in the cardiac cell

The heart pumps blood around the body, delivering nutrients to and removing waste products from every organ. Its function is finely tuned to respond to the demands of the body. My research focuses on the mechanisms which control the behaviour of individual cardiac muscle cells in the heart in response to a variety of stimuli. This information can be used to understand the function of the heart in both health and disease.


Caveolae and G-protein coupled receptor signalling

The way that the heart functions in a healthy individual is a result of a balance between the stimulatory sympathetic nervous system and the inhibitory parasympathetic system. These 2 systems work through different receptors (β-adrenoceptors and muscarinic receptors), but many of the components of the downstream signalling pathways are the same. I am interested in how cellular signalling is controlled to allow these receptors to produce such diverse functional responses. One structure that contributes to this is the caveola, which is a small flask shaped pocket in the cell membrane enriched in cholesterol and lined with the protein caveolin (see Figure). Caveolae can concentrate or exclude components of signalling pathways so as to modulate both the efficiency and fidelity of signal transduction. Our recent work shows the first direct evidence for compartmentalisation of β-receptor signalling by caveolae in the adult cardiac myocyte.



 

Caveolae: organising membrane invaginations
Caveolae are specialised lipid rafts enriched in cholesterol and sphingolipids, characterised by the presence of caveolin and cavin proteins. On the left is an electron micrograph of caveolae in the surface membrane of a cardiac muscle cell. On the right, a cartoon of a caveolae depicting the organisation of caveolin (red) and cavin (green) proteins. Cartoon courtesy of Tim Lee (Faculty of Biological Sciences).


Caveolae and disease

Understanding the remodelling of the failing heart with a view to reversing this is a major goal in heart failure treatment. Our on-going work is exploring how changes in caveolae may contribute to remodelling in both right and left ventricular models of heart failure.

Caveolae and statins

Statins, prescribed to over 6 million people in the UK each year, inhibit the production of mevalonate, a precursor of cholesterol, and substantially reduce cardiovascular morbidity and mortality. Initially these effects were ascribed entirely to a reduction in atherosclerosis, however a body of evidence is accumulating that statins have other beneficial (so-called ‘pleiotropic’ effects). Because caveolae require cholesterol to exist, we predict that statins will have an impact on caveolae. We are currently investigating the impact of statins on caveolae and caveolae-regulated function in the cardiac cell with the aim of providing essential insight into the direct cardiac effects of these agents.

One of the main side-effects of statin treatment is skeletal muscle pain and weakness, which is usually exacerbated by exercise. This is a major reason for stopping statin therapy and so impacts on cardiovascular health. Surprisingly, despite decades of research, the mechanism for myopathy – and why this selectively affects skeletal (not cardiac) muscle - is not known. This is a focus of current work in the laboratory.

Mechanotransduction
The heart possesses a unique intrinsic ability to regulate its force of contraction in response to circulatory demand. For example, during exercise, the amount of blood returning to the heart increases and stretches the cardiac muscle. This acts as a stimulus for increased contraction, allowing the chambers of the heart to expel this greater volume of blood. Some of the processes which link stretch to increased contraction are not understood. I have identified a number of elements (stretch-activated channels, the NaH exchanger) which contribute to the slow phase of force increase following stretch both in single cardiac myocytes (see Video) and cardiac muscle. Recent work has explored the role that caveolae, which could act as reservoirs of extra membrane recruited upon stretch, play in the mechanotransductive response of the heart.

 

Current Projects

Determination of the mechanism for statin-induced myopathy: The cause and consequences of increased sarcoplasmic reticulum calcium leak’. BHF project grant. Calaghan, Steele, Hopkins. 2013-2016

Establishment of a model of left ventricular hypertrophy and failure. Biomedical Health Research Centre. Calaghan, Deuchars, Steele, Peers. 2012-2013

Characterisation of dynamic changes in caveolar resident proteins during adrenergic signalling using quantitative proteomics. BHF Project grant. Fuller (Dundee), Calaghan 2011-2013

Statins directly affect cardiac myocyte function through cholesterol-dependent and independent mechanisms. British Heart Foundation. Calaghan, Porter.  2009-2013

Recent Projects

The role of caveolae in generating receptor-specific cyclic AMP signals in the adult cardiac myocyte. Medical Research CouncilCalaghan, Harvey (US), Colyer. 2009-2011

Pleiotropic effects of statins on caveolae of the cardiac myocyte. Heart Research UK. Calaghan, Porter 2008-2009

The role of caveolae in mechanotransduction in the adult heart: Location, translocation, interaction and functional significance of stretch-activated signalling components. British Heart Foundation .  Calaghan, White, Porter. 2006-2009

 

Faculty Research and Innovation



Studentship information

Postgraduate studentship areas:

  • Mechanisms of statin-induced myopathy (cardiac and skeletal muscle)
  • Caveolar remodelling in heart failure

See also:

Modules managed

BMSC3138 - Cellular Cardiology

Modules taught

BMSC1103 - Basic Laboratory and Scientific Skills
BMSC1212 - Introduction to Pharmacology
BMSC1213 - Basic Laboratory and Scientific Skills 2
BMSC2117/3302 - Cardio-respiratory Phys & Med Phar
BMSC2233 - Topics in Medical Sciences
BMSC3138 - Cellular Cardiology
BMSC3140 - Advanced Scientific Skills
BMSC3233/35/36 - Advanced Topics II
BMSC3301 - Research Project in Biomedical Sciences

Centre membership: The Multidisciplinary Cardiovascular Research Centre (MCRC)

Group Leader Dr Sarah Calaghan  (Associate Professor in Cardiac Physiology)

Control of signalling in the cardiac cell 

Miss Sabine Lotteau  (Visiting Research Fellow)

Dr Kathleen Wright  (Senior Scientific Officer in Cardiovascular Science)

Supporting laboratory research development, training and management in the department of Cardiovascular Sciences 


Postgraduates

Ruth Norman (Primary supervisor) 80% FTE
Elizabeth Evans (Co-supervisor) 35% FTE