Defining The Genetic And Epigenetic Targets Involved In Serrated Neoplasia Of The Colorectum
Funder
National Health and Medical Research Council
Funding Amount
$324,122.00
Summary
We believe that some colon cancers develop from a type of polyp called a hyperplastic polyp and that many of these polyps contain a specific mutation in a gene called BRAF. We are conducting tumour studies using mouse models that carry different mutated genes to understand their role and importance in the pathway by which these cancer evolve. Understanding this will allows us to develop better treatments for pateints suffering from colon cancer.
Our objective is to understand the biological significance of the interaction between iron and the hormone gastrin. The project's significance to human health lies in the fact that gastrins stimulate growth of the lining of the stomach and colon, accelerate the development of gastrointestinal cancers, and may be involved in iron homeostasis. Recognition that iron is essential for the biological activity of gastrins may allow the development of novel therapies for colon cancer and iron overload.
Transcriptional Complexity Of Cell Cycle Regulated Genes During Cell Division And Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$491,703.00
Summary
Massive scale transcriptome and genome annotation efforts have recently identified all genes encoding the cellular machinery of protein phosphorylation. The size of the molecular network of kinases and phosphatses has been found to be far more complex in mammals than previously reported, with many kinase and phosphatase loci generating, on average, more than 4 transcripts per gene. This grant is aimed at addressing the role of transcriptional complexity in the control of normal cell division and ....Massive scale transcriptome and genome annotation efforts have recently identified all genes encoding the cellular machinery of protein phosphorylation. The size of the molecular network of kinases and phosphatses has been found to be far more complex in mammals than previously reported, with many kinase and phosphatase loci generating, on average, more than 4 transcripts per gene. This grant is aimed at addressing the role of transcriptional complexity in the control of normal cell division and tumorigenesis using a systems wide approach. Rather than relying on the locus based study, this proposal seeks to take a systems biology approach, addressing the functional diversity of the expanded human phosphoregulator proteome, identifying all components of the network that are actively and dynamically expressed in the normal cell cycle and-or tumour progression, and then screening selected novel components for an ability regulate the cell cycle. Such studies will advance our understanding the involvements of the protein phosphorylation machinery in regulating cell division, highlight novel components potentially relevant tumorigenesis and potentially identify new chemotherapeutic targets.Read moreRead less
The objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions, and that ferric ion binding is essential for biological activity. Our unpublished data in mouse models indicates a previously unsuspected reciprocal relationship between plasma NAG concentrations and iron status. The significance of this project to human health lies in the facts that NAG ....The objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions, and that ferric ion binding is essential for biological activity. Our unpublished data in mouse models indicates a previously unsuspected reciprocal relationship between plasma NAG concentrations and iron status. The significance of this project to human health lies in the facts that NAGs act as growth factors for the normal gastric and colonic mucosa, accelerate the development of both gastric and colorectal cancer, and may be involved in iron overload. The specific aims are: (1) to determine whether or not ferric ions are essential for the stimulation of colorectal carcinoma (CRC) development by NAGs in vivo, (2) to develop orally active NAG inhibitors and analogues, and (3) to confirm the relationship between NAGs and iron status in mice and extend these observations to humans. The research design mirrors the specific aims, and utilises the unique combination of skills of the chief and associate investigators. Firstly, agents (desferrioxamine and bismuth ions) known to block the binding of ferric ions to NAGs will be tested as NAG inhibitors in 4 animal models of CRC development. Secondly, orally active relatives of desferrioxamine and structurally modified gastrin fragments will be tested in CRC cells and in animal CRC models as NAG inhibitors and analogues, respectively. Thirdly, serum gastrins will be measured in mice with altered dietary iron uptake, and in patients with iron overload. These studies are expected to confirm the reciprocal relationship between gastrin concentrations and ferric ion homeostasis observed in mice, and to demonstrate that a similar connection exists in humans. Recognition that metal ions are essential for the biological activity of NAGs may permit the development of novel therapies for colon cancer and iron overload.Read moreRead less
The Mechanism Of Action Of Progastrins In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$378,000.00
Summary
Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind ga ....Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind gastrin precursors to the surface of colon cells, and to understand how receptor binding triggers changes in the colon which result in CRC development. Our recent discovery that gastrin precursors promote cell migration by reducing adhesion between cells is particularly significant from the perspective of CRC because of the potential importance of this phenomenon in the early stages of cancer development. Our recent observation that gastrin precursors bind metal ions with high affinity further suggests that metal binding may be essential for receptor binding and hence for biological activity. We will therefore investigate: (1) whether binding of metal ions to gastrin precursors effects biological activity, (2) which regions of gastrin precursors are required for receptor binding, (3) the structures of the receptors which bind gastrin precursors to colon cells, (4) the pathways which connect the receptors to other intracellular proteins that maintain contact between adjacent cells, and (5) the differences between the pathways controlling adhesion and the pathways controlling cell growth. This project should lead to a detailed understanding of the molecular mechanisms underlying the effect of gastrin precursors on colon cell growth and adhesion. Definition of the receptors and intracellular signalling mechanisms involved may ultimately lead to novel treatments for disorders of colonic proliferation including CRC.Read moreRead less