Progastrin Derived Peptides: Biological Activities And Functions In The Gastrointestinal Tract
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Gastrin is a hormone from the stomach which aids digestion by stimulating acid secretion. However too much acid can cause ulcers of the gastrointestinal tract. Gastrin also stimulates the growth of the lining of the stomach and intestines. This growth promoting effect is important for the development of the gastrointestinal tract before birth and may also be involved in a number of cancers especially colon cancer. Several different forms of gastrin are made by endocrine cells of the stomach and ....Gastrin is a hormone from the stomach which aids digestion by stimulating acid secretion. However too much acid can cause ulcers of the gastrointestinal tract. Gastrin also stimulates the growth of the lining of the stomach and intestines. This growth promoting effect is important for the development of the gastrointestinal tract before birth and may also be involved in a number of cancers especially colon cancer. Several different forms of gastrin are made by endocrine cells of the stomach and by cancers of the colon. It seems that the different types of gastrins have different effects and act through distinct receptors, but we do not know which are the most important forms and whether all forms are biologically active. The amount, type and activity of the different gastrins, and the regions of the molecule that are essential for biological activity, will be investigated using cell lines, animal models that overproduce too much gastrin, animal models of colon cancer and in patients with colon cancer. Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. A successful outcome will result in the development of assays for the early diagnosis and monitoring of bowel cancer and the potential for novel treatments such as gastrin receptor antagonists and radiolabelled gastrin analogues for radiotherapy.Read moreRead less
Detecting Bioactivity In A Naturally-occurring Aggrecan Fragment
Funder
National Health and Medical Research Council
Funding Amount
$407,634.00
Summary
The dynamic balance of anabolic and catabolic processes in healthy cartilage is disturbed in arthritis, with increased catabolism leading to irreparable cartilage damage. We will study the ability of a naturally-occuring aggrecan fragment to modulate cartilage catabolism. Our in vitro and in vivo experiments suggest that the aggrecan fragment limits cartilage destruction. This study tests our hypothesis that the aggrecan fragment antagonises cartilage damage and promote cartilage repair.
Development Of A Generic Strategy For The Stabilisation Of Peptide-based Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$443,196.00
Summary
There is huge interest in the development of bioactive peptides and proteins for the treatment of a wide range of diseases. However, there are still a number of hurdles that need to be overcome before this source of promising pharmaceuticals can fulfil their vast potential. One of the biggest challenges in the development of peptides and proteins as drugs is overcoming their poor stability in the human body. The broad aim of this research proposal is to develop a novel strategy that provides the ....There is huge interest in the development of bioactive peptides and proteins for the treatment of a wide range of diseases. However, there are still a number of hurdles that need to be overcome before this source of promising pharmaceuticals can fulfil their vast potential. One of the biggest challenges in the development of peptides and proteins as drugs is overcoming their poor stability in the human body. The broad aim of this research proposal is to develop a novel strategy that provides therapeutically promising peptides and proteins the ability to resist the body s natural degradation pathways so they are able to reach their biological target. To develop this strategy we will use the recently discovered peptide hepcidin as a model system. Hepcidin is the major iron-regulatory hormone in the human body and incorrect levels of this hormone result in either iron overload (haemochromatosis), when there is not enough hepcidin produced by the body, or anemia of inflammation when there is too much hepcidin. The development of hepcidin-based therapeutic agents to treat these conditions has the potential to have significant impact as it has been estimated that up to 1 in 300 Australians are affected by haemochromatosis during their lifetimes. Unfortunately, unmodified peptides, like hepcidin, are of limited therapeutic value due to their poor stability within the human body. This research proposal describes the development of stabilised hepcidin analogues with the potential of being useful drug leads for the treatment of haemochromatosis.Read moreRead less
Specific Roles Of The Transmembrane Exoloops And The LDLa Module In The Activity Of Relaxin And INSL3 Receptors
Funder
National Health and Medical Research Council
Funding Amount
$598,863.00
Summary
The peptide hormone relaxin is currently in clinical trials to treat acute heart failure. The related hormone INSL3 has important roles in fertility. We will continue our previously successful approaches to study the interaction of relaxin and INSL3 with their cell surface receptors and the mechanisms by which the receptors function. The knowledge gained will aid in the design of smaller, more potent and orally active forms of relaxin and INSL3 for future clinical applications.
Chondrocyte Hypertrophy In Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$360,018.00
Summary
Whereas chondrocyte hypertrophy is a normal feature of skeletal growth, in adult chondrocytes it is associated with osteoarthritis (OA). We propose that collagen II fragments provide signals for hypertrophy in cartilage. The lack of collagen II fragments in our collagenase-resistant mouse provides a unique opportunity to address the role of collagen II fragments in driving cellular hypertrophy. We will identify bioactive collagen II fragments that represent novel targets for OA therapies
Peptides Derived From ProGRP As Growth Factors For Gastrointestinal Cancers
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Our objective is to determine the roles of a growth factor termed bombesin. This peptide, known as GRP in the human, is a growth factor in certain lung cancers but little is known about its role in tumours of the colon. This project is based on our novel observation that the precursor of GRP (proGRP) previously thought to be inactive is in fact active in stimulating the growth of colon cancer cells. A successful outcome will result in novel treatments such as proGRP antagonists.
The Contribution Of Upstream Open Reading Frames To The Eukaryotic Proteome
Funder
National Health and Medical Research Council
Funding Amount
$197,911.00
Summary
This project will investigate the novel idea that genomes of complex organisms (including human) 'double-dip' with many genes containing information for more than one protein. It will also examine if these small supernumary proteins have cell regulatory functions. If proved, it would significantly alter current views on the information content of higher vertebrate genomes. An understanding of the roles of these novel protein sequences may result in the development of new drugs.
Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. Colorectal carcinomas in common with other cancer types such as cancer of the prostate and lung often produce their own growth factors and receptors. Activation of the receptor by the growth factor further stimulates the tumour's growth and spread throughout the body. The objective of this project is to deterrmine the potential roles of a growth factor termed bombesin. This peptide, now known as GRP ....Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. Colorectal carcinomas in common with other cancer types such as cancer of the prostate and lung often produce their own growth factors and receptors. Activation of the receptor by the growth factor further stimulates the tumour's growth and spread throughout the body. The objective of this project is to deterrmine the potential roles of a growth factor termed bombesin. This peptide, now known as GRP in mammalian systems, is an established growth factor in certain lung cancers but little is known about its role in tumours of the large bowel. This project is based on our novel observation that the precursor of GRP (proGRP) previously thought to be inactive is in fact biologically active in stimulating the growth of colorectal carcinoma cells. We will determine which parts of the GRP precursor (proGRP) are bioactive, and test the effects of the bioactive regions on growth and cancer spread using a variety of colorectal cancer cell lines. We will also investigate the effects of the bioactive regions of proGRP on the development of colorectal cancer in three animal models, which represent different stages of the progression to invasive cancer. We will then compare the intracellular pathways by which proGRP and GRP communicate with the cell nucleus, and investigate the structure of the cell-surface receptor that binds the proGRP. Finally we will determine the types and amounts of proGRP derived peptides produced by CRC cell lines and by tumours obtained from patients with colorectal cancer. A successful outcome will result in the development of assays for the early diagnosis and monitoring of bowel cancer and the potential for novel treatments such as proGRP receptor antagonists and radioactive proGRP analogues for radiotherapy.Read moreRead less
Physiology And Pathology Of Novel Forms Of Progastrin
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
Gastrin is a stomach hormone which increases acid secretion and the growth of the stomach and bowel. This growth promoting effect may be involved in a number of cancers especially colon cancer. The different types of gastrins have different effects but we do not know which forms are important and whether all are active. The types and activity of the different gastrins will be investigated using cell lines, animal models and colon cancer patients with the view of establishing new treatments.
Bombesin Like Peptides As Autocrine Growth Factors In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. Colorectal carcinomas in common with other cancer types such as cancer of the prostate and lung often produce its own growth factors and receptors. Activation of the receptor by the growth factor further stimulates the tumour's growth and spread throughout the body. The objective of this project is to determine the potential roles of a growth factor termed Bombesin Like Peptide. This peptide, now kn ....Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. Colorectal carcinomas in common with other cancer types such as cancer of the prostate and lung often produce its own growth factors and receptors. Activation of the receptor by the growth factor further stimulates the tumour's growth and spread throughout the body. The objective of this project is to determine the potential roles of a growth factor termed Bombesin Like Peptide. This peptide, now known as GRP in mammalian systems, is an established growth factor in certain lung cancers but little is known about its role in tumours of the large bowel. We will study the expression and production of GRP and its receptors at the gene and protein level, the ability of GRP to stimulate growth, the chemical structures of GRP, and the potential of antagonists of GRP to modulate growth. Studies will be performed in patients with bowel cancer, in animal models of bowel cancer, and with bowel tumours removed from patients and bowel cancer cell lines. A successful outcome will result in the development of assays for the early diagnosis and monitoring of bowel cancer and the potential for novel treatments such as GRP receptor antagonists and radiolabelled GRP analogues for radiotherapy.Read moreRead less