Regulatory Peptides Research Group
The Regulatory Peptides Research Group is headed by Prof Arthur Shulkes and Assoc Prof Graham Baldwin which focuses on the mechanisms by which peptide growth factors stimulate the growth of the normal gastrointestinal mucosa and the development of gastrointestinal and other cancers. At present we are concentrating on two structurally un-related growth factors, gastrin and gastrin-releasing peptide. Our long term goal is to design and test new therapies for colorectal carcinoma (CRC). As the same growth factors are probably involved in other cancers we are also investigating prostate and renal cancers.
The gastrin field has been revolutionised in the past decade by the discovery that non-amidated gastrins (NAGs) have a completely different spectrum of biological activities from mature amidated gastrin (1). Studies from several laboratories including our own have shown that, as well as stimulating the proliferation and migration of a variety of cell lines in vitro (2), NAGs promote proliferation of the colonic mucosa, and accelerate CRC development in vivo. Clinical studies have shown that CRC produce NAGs, that circulating concentrations of NAGs are increased in patients with CRC, and that a circulating gastrin concentration above normal was associated with a 3.9-fold greater risk of developing CRC.Despite the potential importance of these discoveries it is not clear which are the bioactive NAGs, the structure of the receptor(s) responsible remains undefined, and no selective antagonists are available.
We recently demonstrated that gastrins selectively bind two Fe3+ ions with high affinity, and that binding of Fe3+ ions is essential for the biological activity of NAGs. These observations stimulated a reappraisal of the role of gastrins in metal ion homeostasis, which led to our unexpected observation that circulating gastrin is increased in animals and humans with iron overload (5). We are currently investigating whether alteration of gastrin expression results in reciprocal changes in iron homeostasis.
Gastrin-releasing peptide (GRP) was initially discovered in the stomach, and named for its potent stimulation of gastrin release (3). However the widespread distribution of GRP, with significant amounts present in the central nervous system and throughout the entire gastrointestinal tract, suggests more general actions. In particular GRP has been recognised as the prototypical autocrine growth factor, based on the detection of GRP and its cognate receptor in small cell lung carcinoma (SCLC). GRP is also a potent mitogen for several other types of carcinomas including colorectal, pancreas, prostate, and breast. Although it has been assumed that bioactive GRP peptides are derived exclusively from residues 1-27 of the GRP precursor proGRP, peptides derived from the C-terminus of proGRP are present in normal and tumour tissues. We have expressed several C-terminal fragments of proGRP in bacteria, and are now investigating their biological activities in vitro (6), and in animal models of CRC. We are also investigating the role of the GRP peptides in prostate and renal carcinomas.
The laboratory is funded through multiple NHMRC Project Grants, through the Austin Hospital Medical Research Foundation, and through a NIH (USA) Project Grant “The Biology of Gastrin-Ferric Ion Complexes” held by Assoc. Prof. Graham Baldwin with Prof. Shulkes, Assoc. Prof. Greg Anderson (Queensland Institute for Medical Research), Prof. Ray Norton (the Walter and Eliza Hall Institute) and Prof. Ted Baker (University of Auckland).
Research Staff
top of page- Head: Professor Arthur Shulkes
Tel: +613 94965482
Email: aas@unimelb.edu.au - Associate Professor Graham Baldwin
- Dr Hong He (Senior Research Officer)
- Dr Oneel Patel (Research Officer)
- Dr Audrey Ferrand (Research Officer)
- Mildred Yim (Research Assistant)
- Ioulia Sims (Research Assistant)
- Rachele Lockie (Research Assistant)
Higher Degree Students
top of page- Nezor Houli (MSurg) Effects of Bombesin/Gastrin Releasing Peptides on the Development of Colorectal Carcinoma: A Rat Model.
- Su-Wen Loh (MSurg) Role of Growth Factors in the Development of Gastrointestinal Cancers.
- Thang Chien Nguyen (MD) Ischaemia Reperfusion Injury of the Rat Liver.
- Suzana Kovac (PhD, 2006 – 2008) The Role of Ferric Ions in the Biological Activity of Gastrins.
- Joseph Ischia (PhD, 2007 – 2010) GRP and its Role in Renal Carcinogenesis.
- Gianni Bramante (PhD, 2007 – 2010) Growth Factors and Gastrointestinal Cancer.
Graduating Students
top of pageResearch Higher Degree and Undergraduate Degree graduating students are listed on the graduating students page.
Publications
top of pageResearch Publications from 2003 onwards are available on the Research Publications page.
Funding
top of pageDetails of research funding from 2003 onwards is available from the Research Funding page.