Professor Robert M Graham, FAA MD FRACP FACP FAHAExecutive Director, Victor Chang Cardiac Research Institute
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Research Focus:
We are currently involved in structure/function studies of a1-adrenergic receptors (a1-AR) and the novel coupled G-protein, Gh; involvement of a1-ARs and Gh in cardiac hypertrophy and arrhythmias; molecular mechanisms of cardiac hypertrophy and potential of stem cells for the treatment of cardiac disorders.
Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. Over 80% of such stimuli are mediated by G-protein-coupled receptors (GPCRs), and they are the targets of over 50% of available therapeutics. We have had a long-standing interest in the molecular characterisation and signaling pathways of adrenergic receptors, particularly the a1-AR family of GPCRs.
A major thrust in this regard is studies of a1-AR structure and function using site-directed mutagenesis, biochemical, biophysical, macromolecular modelling and cell biology approaches. These studies are aimed at elucidating the molecular mechanisms of receptor activation and inactivation.
Of recent interest is the development of signal inactivating point mutations that induce dominant negative activity by allowing binding, but not activation of their cognate G-proteins. Structure-function studies to investigate the catalytic mechanism and physiology of Gh (Tgase II) are also being pursued using mutagenesis, biochemical and x-ray crystallographic (the latter in collaboration with Prof. Michael Parker) approaches. Concurrently the role of these receptors and their coupled signalling pathways in cardiac function and disease, and of contractile proteins, are being undertaken using transgenic and gene targeting technologies, involving the Tet repressor/transactivator and Cre/lox systems to produce conditional transgenesis and tissue specific gene inactivation, respectively.
Finally, we are undertaking clinical and basic studies of stem cells to evaluate their potential in the treatment of cardiac disorders such as ischaemia and heart failure.
Co-Investigators:
Sharon Chih, MBBS
Sara Holman, BMedSc
Siiri Iismaa, PhD
Kristy Jackson, BSc
Pei Wen Lei, MSc
Chu-Kong Liew, PhD
Marion Mohl, PhD
R. Peter Riek, PhD
Jianxin Wu, PhD
Ting Wai Yiu
Collaborators:
John Bremner, PhD; University of Wollongong, Wollongong, Australia
Gail VW Johnson, PhD; University of Alabama, Birmingham, USA
Laszlo Lorand, MD; Northwestern University Medical School, Chicago, USA
Michael Parker, PhD; St. Vincent's Institute of Medical Research, Melbourne
Xiao-Jun Du, MBBS PhD; Baker Institute of Medical Research, Melbourne
Susan Steinberg, MD; Columbia University, New York, USA
Arthur J. L. Cooper, PhD, DSc; Cornell University, New York, USA
Selected Publications:
Nakaoka H, Perez DM, Baek KJ, Das T, Husain A, Misono K, Im MJ, Graham RM. Gh: A GTP-binding protein with transglutaminase activity and receptor signaling function. Science 1994; 264:1593-1596
Semsarian C, Wu MJ, Ju YK, Marciniec T, Yeoh T, Allen DG, Harvey RP, Graham RM. Skeletal muscle hypertrophy is mediated by a Ca2+ dependent calcineurin signaling pathway. Nature 1999; 400:576-581
Chen S, Lin F, Xu M, Hwa J, Graham RM. Dominant negative activity of an alpha1B-adrenergic receptor signal inactivating point mutation. EMBO Journal 2000; 19:4265-4271
Lin F, Owens WA, Chen S, Stevens ME, Kesteven S, Arthur JF, Woodcock EA, Feneley MP, Graham RM. Targeted alpha1A-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy. Circulation Research 2001; 89:343-350
Riek RP, Rigoutsos I, Novotny J, Graham RM. Non-a-helical elements drive diversity of polytopic membrane protein architecture. Journal of Molecular Biology 2001; 306:349-362
Fatkin D, Graham RM. Molecular mechanisms of inherited cardiomyopathies. Physiological Reviews 2002; 82:945-980
Iismaa SE, Holman S, Wouters MA, Lorand L, Graham RM, Husain A. Evolutionary specialization of a tryptophan indole group for transition-state stabilization by eukaryotic transglutaminases. Proceedings of the National Academy of Sciences (USA) 2003; 2212636-12641
Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nature Reviews Molecular Cell Biology 2003; 4:140-156
Li M, Liu K, Michalicek J, Angus JA, Hunt JE, Dell'Italia LJ, Feneley MP, Graham RM, Husain A. Involvement of chymase-mediated angiotensin II generation in blood pressure regulation. J Clin Invest 2004; 114:112-120
Kovacic JC, Graham RM. Stem-cell therapy for myocardial diseases. Lancet 2004; 363:1735-1736
Begg GE, Carrington L, Stokes PH, Mathews JM, Wouters MA, Husain A, Lorand L, Iismaa S, Graham RM. Mechanism of allosteric inhibition of transglutaminase 2 by GTP. Proc Natl Acad Sci (USA) 2006; 103:19683-19688
Strnad P, Harada M, Siegel M, Terkeltaub RA, Graham RM, Khosla C, Omary MB. Transglutaminase 2 regulates mallory body inclusion formation and injury-associated liver enlargement. Gastroenterology 2007; 132:1515-1526
Ju YK, Chu Y, Chaulet H, Lai D, Gervasio OL, Graham RM, Cannell MB, Allen DG. Store-operated Ca2+ influx and expression of TRPC genes in mouse sinoatrial node. Circ Res 2007; 100:1605-1614
Li M, Naqvi N, Yahiro E, Liu K, Powell PC, Bradley WE, Martin DI, Graham RM, Dell'Italia LJ, Husain A. c-kit is required for cardiomyocyte terminal diffrentiation. Circ Res 2008; 40:663-669
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