BBSRC David Phillips Fellow Tel: +44 (0)1223 333815(office), 333891(lab), Fax: +44 (0)1223 333840, E-mail: jaf21@cam.ac.uk
Fellow (College Lecturer in Medicine) of Gonville and Caius College.
We are interested in how movements are controlled by neural circuits. Our everyday movements are performed with little conscious thought and are remarkably precise. Despite what the textbooks tell you, the neural mechanisms by which this is accomplished are poorly understood. We work at several levels, particularly at the spinal cord and cerebellum.
Research Interests: I am interested in cardiac and skeletal muscle electrophysiology. My group uses a combination of computer modelling and experimental work to fully understand the mechanisms underlying both the normal and the pathological behaviours of these tissues. As described below, the use of computer modelling allows us to exploit interesting and helpful synergies between skeletal and cardiac muscle research, accelerating our progress considerably.
Cardiac electrophysiology: Our recent work has focused on the consequences of abnormal Ca2+ homeostasis for cardiac function. We have shown that increased diastolic Ca2+ produces a significant decrease in action potential conduction velocity in both atria (1) and ventricles (2), and that there is a significant correlation between slowed conduction and arrhythmogenicity. This finding directly suggests novel strategies for research, diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT) (see e.g. here), as described in two recent editorials on our papers (here and here).
Skeletal muscle electrophysiology: My work with skeletal muscle forms two broad streams. The first aims to feed findings into my group's cardiac research, while the second is aimed at understanding skeletal muscle electrophysiology with direct relevance to human diseases. The recent focus of the first stream has been on understanding the determinants of conduction velocity in muscle. We have been able to show precisely how conduction velocity is determined and how it is influenced by changes in structure and electrophysiology in health and disease (4, 5). This has informed our work exploring the mechanisms linking abnormal cardiac Ca2+ homeostasis and conduction slowing. Our work in the second stream has recently provided insight into the phenotypic variation in myotonia congenita.
Please
see the Research, Teaching and Contact tabs above for further
details.
Funding: I am very grateful for the following generous funding:
David Phillips Fellowship from the BBSRC.
Royal Society / National Science Foundation of China International Collaboration Grant
Main Collaborators:
Prof Chris Huang, Department of Physiology, Development and Neuroscience, University of Cambridge.
Assoc Prof Thomas Pedersen, Institute of Physiology and Biophysics, University of Aarhus, Denmark.
Prof Aiqun Ma, Department of Cardiovascular Medicine, Xi'an Jiaotong University, China.
Prof Ron Horgan, Department of Applied Mathematics and Theoretical Physics, University of Cambridge.
Dr Ming Lee, Institute of Cardiovascular Science, University of Manchester.
Dr Yanmin Zhang, Institute of Cardiovascular Science, University of Manchester.
Dr Andrew Grace, Department of Biochemisty, University of Cambridge.
To download a full list of my publications in Word format please click here, or see a linked version using ResearchGate or Google Scholar
I am interested in the electrophysiology of cardiac and skeletal
muscle. My aim is to advance understanding of the normal and
pathological behaviours of these tissues in order to improve the
diagnosis and treatment of cardiac arrhythmias and skeletal muscle
pathologies.
My group's strategy is built on a foundation of novel quantitative and experimental techniques that allow continuous cycles of computational analysis, experimental testing and translational assessment. The key theoretical advance has been the development of charge-difference modelling. This allows history-independent modelling (see Figure 1); that is to say, the eventual steady state of the model is independent of the initial value of its variables.
Recent work
My
group's recent work has focused on Ca2+
homeostasis in muscle.
In cardiac muscle, abnormalities of intracellular Ca2+ homeostasis are found in common and medically-important conditions as diverse as cardiac failure, atrial fibrillation and cardiac ischaemia. We have employed a model of catecholaminergic polymorphic ventricular tachycardia (CPVT), the RyR2-P2328S mouse, in order to study abnormal Ca2+ homeostasis in isolation. We then aim to apply what we learn in this important, though rare condition to understand the influence of abnormal Ca2+ homeostasis within the more complex multifactorial abnormalities that occur in more common conditions such as atrial fibrillation.
We
have found that increased diastolic Ca2+
increases the incidence of both atrial and ventricular arrhythmias (King
et al, 2012; Zhang
et al, 2012). This is true whether the
increased diastolic Ca2+ is brought about
acutely, for example with caffeine, or chronically, as a result of a
gain-of-function mutation in the cardiac ryanodine receptor
(RyR2-P2328S). Using a multielectrode array (click to see image)
we demonstrated a reduction in myocardial conduction velocity in
RyR2-P2328S hearts. We further showed that this increased the risk that
an ectopic stimulus would produce a sustained arrhythmia. This work,
and its implications, is well summarized in two recent editorials (here
and here).
In skeletal muscle, we have studied the influence of the transverse tubular system on excitability, conduction velocity and ionic homeostasis. We first developed models of skeletal muscle (Pedersen et al, 2011; Fraser et al, 2011) that allowed us to describe the complex interactions between surface and transverse-tubular electrical activity and changes in ion concentrations during repetitive activity. The models allowed us to use experimental work to indirectly measure some important variables that are otherwise impossible to directly measure, including the rapid changes in K+ concentration in the transverse tubular system during exercise.
This
strong theoretical framework has allowed us to understand pathologies
in which there are severe abnormalities of skeletal muscle
electrophysiological homeostasis, including myotonia congenita
and myasthenia gravis, and thereby begin in
vitro testing of possible therapies for these diseases. The
first outputs of this work-stream will be published imminently, so
watch this space...
Previous landmark findings from my research include:
A full quantitative description of the
determinants of cell volume and the resting potential (Fraser &
Huang, 2004.) We highlighted the importance of the osmolality and the
mean charge of membrane impermeant anions in determining cell volume
and the membrane potential.
Further modelling suggested that intracellular acidification would cause cellular shrinkage due to titration of the charges carried by membrane-impermeant intracellular anions. We confirmed this by demonstrating that intracellular acidification causes cell volume reduction and K+ loss: see Figure 2, (from Fraser, Middlebrook et al, 2005.)
The discovery that skeletal muscle regulates its membrane potential at the expense of its cell volume during osmotic stress (Ferenczi, Fraser et al, 2005; Fraser, Rang et al, 2005.)
To download a full list of my publications, please click here.
Here,
I provide some useful links for my students:
Part 1A
Supervisions for 1A homeostasis.
Link
to Transkills: excellent guide to essay writing for bioscience
students, inter alia.
Lectures
in renal physiology and body fluid homeostasis (6 lectures, Lent term).
Links will come live during the lectures.
Part 1B
Lectures in muscle physiology.
Part II
Computer
modelling links from the practical class associated with the lectures:
How to construct a Hodgkin-Huxley nerve model in Excel.
Suggestions
for using and "improving" the HH model in Excel as exercises.
An Excel version of the Hodgkin-Huxley nerve model.
An Excel model
of the Hodgkin-Huxley nerve model with cable conduction.
E-mail:
jaf21@cam.ac.uk
Office:
A4, Physiological
Laboratory.
Tel: +44 (0)1223 333815
Fax: +44 (0)1223 333840
Lab: A2, A1: Tel: 33891
College: K12, St. Mary's Court, Gonville & Caius College
Tel: 01223 701328
Online: ResearchGate
I will be pleased to consider applications from prospective PhD students by email.
© 2013 University of Cambridge