Role of calcitonin receptor in stressed cells and diseased tissues: a new paradigm based on expression in the pre-apoptotic cell stress response
Research in our laboratory has discovered an important role for calcitonin receptor (CTR) in the adaptive response of cells to stress that precedes the onset of apoptosis . Expression of CTR has been found in stressed tissues in cardiovascular disease such as unstable atheroscerotic plaque, in wound healing and in particular cancers. Specific antibodies against extracellular and intracellular epitopes of CTR have been developed. Utilities of these antibodies that are under development here include imaging programmed cell death (PCD) in vitro and in vivo, the reduction in tumour size of models of the brain tumour glioblastoma and the definition of intracellular events that form the basis of CTR involvement in cell stress and PCD.
A further interest is the characterization of an antibody target that is thought to represent a high affinity ligand of CTR in human cells. This protein has been identified on immunoblots and by confocal microscopy with a unique antibody developed in our laboratory. On-going research is directed towards the purification of the target protein, its sequence and the full description of the associated molecular biology.
- Dr Roger Gilabert-Oriol, Postdoctoral Researcher
- Mrs Angela Kourakis, Research Assistant
- Dr Sebastian Furness, Drug Discovery Laboratories, Monash University, Royal Parade, Parkville: Pharmacological studies to evaluate the molecular mechanisms of agonist bias that determines the output of the calcitonin receptor.
- Dr Catarina Potes, Department of Experimental Biology, Faculty of Medicine of the University of Porto Al. Hernâni Monteiro, 4200-319 Porto Portugal: (1) The mapping of CTR-positive neurons in the spinal cord and DRGs in animal models, and (2) The expression of CTR in medullary thyroid tumours.
- Professor Hendrik Fuchs, Institute for Laboratory Medicine, Charite-UniversiteMedizin, Berlin, Germany: Enhancer therapy to improve efficacy of novel immunotoxins in the treatment of glioblastoma.
- Associate Professor Hui Gan and Prof Andrew Scott, Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute: The testing of anti-CTR immunotoxin to restrict sc. tumour expansion in mouse xenograft models.
Postdoc support from the Australian government, philanthropic funds, funds from the pharmaceutical industry and small institutional grants.
- Gilabert-Oriol R, Weng A, Trautner A, Weise C, Schmid D, Bhargava C, Niesler N, Wookey PJ, Fuchs H, Thakur M. Combinatorial approach to increase efficacy of Cetuximab, Panitumumab and Trastuzumab by dianthin conjugation and co-application of SO1861. Biochem Pharmacol 2015;97(3): 247-255.
- Bullock CM, Wookey PJ, Bennett A, Mobasheri A, Dickerson I, Kelly S. Increased peripheral calcitonin gene-related peptide receptor signalling drives mechanical sensitization of the joint in rat models of osteoarthritic pain. Arthritis & Rheumatology 2014;66(8): 2188-2200.
- Sharma V, Ling TW, Rewell S, Howells DW, Hare DL, Kourakis A, Wookey PJ. A novel population of α–smooth muscle actin –positive cells activated in a rat model of stroke: an analysis of the spatio-temporal distribution in response to ischaemia. J Cerebral Blood Flow Metab 2012;32(11): 2055-2065.
- Wookey PJ, Turner K, Furness J. Transient expression of the calcitonin receptor by enteric neurons in the embryonic and immediately post-natal period in the mouse. Cell Tissue Res 2012;347: 311-317.
- Wookey PJ, McLean CA, Hwang P, Furness SGB, Nguyen S, Kourakis A, Hare DL, Rosenfeld JV. The expression of calcitonin receptor detected in malignant cells of the brain tumour glioblastoma multiforme and functional properties in the GBM cell line A172. Histopathol 2012;60: 895-910.
- Wookey PJ, Zulli A, Lo C, Hare DL, Schwarer AP, Darby IA, Leung A. Calcitonin receptor (CTR) expression in embryonic, foetal and adult tissues: developmental and pathophysiological implications. In: “The calcitonin gene-related peptide family; form, function and future perspectives”, Eds Debbie L Hay & Ian M Dickerson. Netherlands: Springer. 2010, pp199-233 [ISBN: 978-90-481-2908-9].
- Wookey PJ. A review of calcitonin receptor expression in embryonic, foetal and adult tissues with a hypothesis on the connection between expression during foetal development and disease. TheOpenZoology Journal 2009;2: 77-85.
- Wookey PJ, Zulli A, Hare DL. The elevated expression of calcitonin receptor by cells recruited into the endothelial layer and neo-intima of atherosclerotic plaque. Histochem Cell Biol 2009;132 (2): 181-9.
- Wookey PJ, Zulli A, Buxton BF, Hare DL. Calcitonin receptor immunoreactivity associated with specific cell types in diseased radial and internal mammary arteries. Histopathol 2008;52: 605-612.
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