While fluorescence-based techniques can be applied to the study of disease at a fundamental mechanistic level, e.g. using molecular cell biology techniques with highly specific labels, including genetically expressed fluorescent proteins, they can also be applied to preclinical and clinical studies. Preclinical studies in animal models are an essential precursor to clinical studies and form a significant part of the drug discovery pipeline. Following the principles of the 3Rs in biomedical research, it is essential to minimise the number of animals used for medical research and to maximise the information that can be gained from each experiment. It is therefore important to develop new methods that can help increase the effectiveness of animal studies and minimise the impact on the subject. In the Photonics Group we aim to help achieve this goal by developing new fluorescence based-instrumentation, for example to provide minimally invasive measurements that can enable longitudinal studies thereby significantly reducing the numbers of animal experiments needed.
For preclinical studies we are mainly developing fluorescence-based instrumentation that can complement established preclinical imaging technologies, such as X-ray CT, PET, MRI etc., and are particularly interested to translate quantitative readouts of cell function from microscopy of cell cultures to disease models. Although we have made some progress developing non-invasive readouts of cell function in murine disease models, most of our current in vivo efforts are directed towards imaging disease processes in zebrafish. We have also worked to apply our multidimensional fluorescence imaging technologies to ex vivo tissue samples, particularly in studies of the pancreas for diabetes research.
The following are some specific topics or projects that we have addressed in preclinical studies as part of our mission to understand the mechanism of disease in order to further the development of therapies. All animal studies at Imperial College London are undertaken under a rigorous regulatory and ethical framework and are carried out by our biomedical collaborators.
Ex vivo imaging or metrology of tissue
G. Sun, A. I. Tarasov, J. McGinty, A. McDonald, G. D. Xavier, T. Gorman, A. Marley, P. M. French, H. Parker, F. Gribble, F. Reimann, O. Prendiville, R. Carzaniga, B. Viollet, I. Leclerc, and G. A. Rutter, "Ablation of AMP-activated protein kinase alpha 1 and alpha 2 from mouse pancreatic beta cells and RIP2.Cre neurons suppresses insulin release in vivo," Diabetologia 53, 924-936 (2010)
LKB1 deletion with the RIP.Cre-transgene modifies pancreatic beta-cell morphology and enhances insulin secretion in vivo, G. Sun, A. I. Tarasov, J. A. McGinty, P. M. French, A. McDonald, I. Leclerc, and G. A. Rutter, American Journal of Physiology-Endocrinology and Metabolism 298, E1261-E1273 (2010)
Abnormal oral glucose tolerance and GLP-1-induced insulin secretion in pancreas-specific Tcf7l2 null mice, G. da Silva Xavier & A. Mondragon & G. Sun & L. Chen & J. A. McGinty & P. M. French & G. A. Rutter, Diabetologia 55 (2012) 2667–2676, DOI 10.1007/s00125-012-2600-7
Animal Models of GWAS-Identified Type 2 Diabetes Genes, Gabriela da Silva Xavier,1 Elisa A. Bellomo,1 James A. McGinty, Paul M. French,2 and Guy A. Rutter, Journal of Diabetes Research, Volume 2013, Article ID 906590, 12 pages, DOI: 10.1155/2013/906590
Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass, Ryan K. Mitchell, Angeles Mondragon, Lingling Chen, James A. McGinty, Paul M. French, Jorge Ferrer, Bernard Thorens, David J. Hodson, Guy A. Rutter, and Gabriela da Silva Xavier, Hum Mol Genet 24 (2015) 1390-1399
In vivo fluorescence lifetime optical projection tomography
J. McGinty, H. B. Taylor, L. Chen, L. Bugeon, J. R. Lamb, M. J. Dallman, and Paul M. W. French
Biomed. Opt. Expr. 2 (2011) 1340-1350
Mesoscopic in vivo 3-D tracking of sparse cell populations using angular multiplexed optical projection tomography, L Chen, Yuriy A, Sunil Kumar, N Andrews, M J. Dallman, P M. W. French* and J McGinty*, Biomedical Optics Express 6 (2015) 1253- 1261, DOI:10.1364/BOE.6.001253
Accelerated Optical Projection Tomography Applied to In Vivo Imaging of Zebrafish”, T. Correia 1, N. Lockwood, S. Kumar, J. Yin, M-C Ramel, N. Andrews, M. Katan, L. Bugeon, M J Dallman, J McGinty*, P. Frankel*, P. M W French* and S. Arridge*, PLoS ONE 10(8): e0136213, doi:10.1371/journal.pone.0136213
Visualising apoptosis in live zebrafish using fluorescence lifetime imaging with optical projection tomography to map FRET biosensor activity in space and time, N. Andrews, M-C Ramel, S. Kumar, Y. Alexandrov, D. J. Kelly, S. C. Warren, L. Kerry, N. Lockwood, A. Frolov, P. Frankel, L. Bugeon, J. McGinty, M. J. Dallman* and P. M. W. French*, Early view J. Biophotonics 1–11 (2016) / DOI 10.1002/jbio.201500258
Imaging and metrology of mammalian disease models
In vivo fluorescence lifetime tomography of a FRET probe expressed in mouse, J. McGinty, D. W. Stuckey, V. Y. Soloviev, R. Laine1, M. Wylezinska-Arridge, D. J. Wells, S. R. Arridge, P. M. W. French, J. V. Hajnal and A. Sardini, Biomed. Opt. Expr. 2 (2011) 1907-1917
Förster Resonance Energy Transfer imaging in vivo with approximated Radiative Transfer Equation
Vadim Y. Soloviev, James McGinty, Daniel W. Stuckey Romain Laine, Marzena Wylezinska-Arridge, Dominic J. Wells, Alessandro Sardini, Joseph V. Hajnal, Paul M.W. French and Simon R. Arridge
Applied Optics 50 (2012) 6583-6590
Application of time-resolved autofluorescence to label-free in vivo optical mapping of changes in tissue matrix and metabolism associated with myocardial infarction and heart failure, J. Lagarto, B. T. Dyer, C. Talbot, M. B. Sikkel, N. S. Peters, P. M. W. French, A. R. Lyon and C. Dunsby, Biomed Opt Express 2015, 6 (2015) 324-346