Identification Of The Pain Pathway From The Rectum And Its Mechanisms Of Activation
Funder
National Health and Medical Research Council
Funding Amount
$566,931.00
Summary
Abdominal pain is one of the most common reasons why patients seek medical attention. It is now known that irritable bowel syndrome (IBS) is one of the major causes of abdominal pain, but the reason why people experience pain from the gut is not known. This project will identify which sensory nerves in the gut wall signal pain to the spinal cord during conditions that mimic IBS and the precise mechanisms that activate these sensory neurons during IBS-like inflammation will be investigated.
Functions Of FZD7 In The Intestine And Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$644,761.00
Summary
Wnt proteins are a family of signaling molecules that are critical for the function of normal and cancerous epithelial cells in the gut. However, the cell surface receptor that transmits Wnt signals is not known. Our research strongly implicates one Wnt receptor (FZD7). Here we test this using innovative mouse and cell line models. We wish to understand how Wnt-driven processes are activated. This knowledge will lead to novel avenues to block aberrant activation of Wnt signalling in cancer cells
The Knotty Problem Of Enterochromaffin Cells And Gastro-intestinal Function: Unravelling Cause And Effect
Funder
National Health and Medical Research Council
Funding Amount
$403,097.00
Summary
It is crucial to understand how the food we eat controls the secretions and movements of a healthy or a diseased gastrointestinal (GI) system. One way control is achieved involves the release of serotonin (5-HT) from the enterochromaffin cells present in the epithelial lining of the intestine. This is the subject of our proposal and our results will help us to understand the causes of GI disorders and help to formulate new treatments.
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.
Cooperative Motor Control Of The Pyloric Junction By Myogenic And Neuronal Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$271,527.00
Summary
The coordinated muscle movement in the junction between the stomach and small intestine is an essential mechanism for controlling the speed of gastric content moving into the intestine for further digestion. The muscle movement determines the gastric emptying at an optimal rate and prevents intestinal contents reflux to the stomach. Failure of this coordination is likely to be involved in a variety of clinical conditions including accelerated or delayed gastric emptying. Up to date, little infor ....The coordinated muscle movement in the junction between the stomach and small intestine is an essential mechanism for controlling the speed of gastric content moving into the intestine for further digestion. The muscle movement determines the gastric emptying at an optimal rate and prevents intestinal contents reflux to the stomach. Failure of this coordination is likely to be involved in a variety of clinical conditions including accelerated or delayed gastric emptying. Up to date, little information is available about the interaction between nerve, muscle and pacemaker cells during this coordinated movement. In this project, we will investigate how the nerve, muscle and pacemaker cells work together to control this coordinated movement. We will study this mechanism at both cellular and organ levels and try to establish the patterns of muscle movement and their coordination between the stomach and the small intestine. The interaction between the nerve and pacemaker cells will be characterised in these studies. Our work will provide structural evidence for this activity. It includes identification of the nerve pathways connecting between the small intestine and stomach and determination of whether the pacemaker cell network is an uniform continuous or a discontinuous or a transitional structure across the junction. These studies will reveal the correlation between pacemaker cell mediated activity and the density of these cells in each junctional region. We will also determine whether the difference in propagation activity across the junction is due to differences in the number of cells for signal conduction or electrical connections between the cells. This study will advance our knowledge for understanding how the nerve, muscle and pacemaker cells work in concert in this junction, which is an important step for further clinical investigation of related disease.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
Gastroduodenal Motility And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach emptying may contribute to a number of problems in diabetes, including sym ....The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach emptying may contribute to a number of problems in diabetes, including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. It is now recognised that the blood glucose level itself has a reversible effect on both stomach contractions and symptoms. For example, when the blood glucose is abnormally high (hyperglycaemia), the rate at which the stomach empties food into the intestine is slower and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of glucose from the intestine affect the rise in the blood glucose level after a meal; this is an important issue because it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the development and progression of the complications of diabetes. In many people with diabetes eating a meal results in a substantial fall in blood pressure, which may cause fainting and falls. By slowing gastric emptying the magnitude of the fall in blood pressure is minimised. Our group has been the recipient of ongoing support from the NH and MRC for approximately 18 years to conduct research in this area. As a result we have performed the most comprehensive studies to date and developed new methods to evaluate stomach and intestinal function in people with diabetes, resulting in international recognition. The studies proposed in the current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less
Mechanics Of Normal And Disordered Gastric Emptying Studied Using Simultaneous Ultrasound And High Resolution Manometry
Funder
National Health and Medical Research Council
Funding Amount
$145,626.00
Summary
Optimal digestion and absorption relies on the stomach breaking down food and delivering it to the small intestine at an optimal rate. Abnormalities in the processes controlling the stomach's processing of food may lead to malnutrition, gastrointestinal symptoms or unpredictable drug absorption, and are commonly seen in patients with diabetes mellitus, gastrointestinal reflux disease and nonulcer dyspepsia, or following stomach surgery. Currently our understanding of the way the stomach empties ....Optimal digestion and absorption relies on the stomach breaking down food and delivering it to the small intestine at an optimal rate. Abnormalities in the processes controlling the stomach's processing of food may lead to malnutrition, gastrointestinal symptoms or unpredictable drug absorption, and are commonly seen in patients with diabetes mellitus, gastrointestinal reflux disease and nonulcer dyspepsia, or following stomach surgery. Currently our understanding of the way the stomach empties food is incomplete, and there is little information as to the mechanisms by which diseases cause abnormal stomach emptying. Recent developments in recording methods mean that we can now simultaneously measure stomach contractions, the pressures these generate and flow from the stomach. This information is synchronised and displayed for analysis using computer techniques. In this project these novel methods will be used initially to examine the normal processes by which meals with a variety of compositions and consistencies empty from the stomach. This will provide information as to which aspects of the way the stomach functions are important for breaking down food into particles, and which aspects control the flow of food from the stomach into the intestine. The mechanisms by which the rate of emptying of the stomach is controlled by feedback signals caused by the presence of foodstuffs in the small intestine will be investigated by examining the effects of infusing nutrients into the intestine on the motions of the stomach wall, pressures within the stomach and the passage of stomach contents into the small intestine. The mechanism of action of drugs and diseases which slow stomach emptying will then be examined by measuring the movements, pressures and emptying of the stomach in subjects receiving the drug, or in patients with dibetes, and comparing this information with the processes observed during normal stomach emptying.Read moreRead less
Gastric Motility And Blood Glucose Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$354,947.00
Summary
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate of which the stomach empties food is slow in up to 50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. It is now recognised that disordered stomach emptying may contribute to a number of problems i ....The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate of which the stomach empties food is slow in up to 50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. It is now recognised that disordered stomach emptying may contribute to a number of problems in diabetes, e.g. symptoms such as nausea and bloating and poor control of blood glucose concentrations. In some people symptoms are disabling and affect quality of life adversely. The effects of stomach emptying on blood glucose control is likely to be important, as it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the development and progression of complications of diabetes. In many people with diabetes, particularly older people with type 2 diabetes, there is a fall in blood pressure after a meal which may result in fainting and falls. The magnitude of the fall in blood pressure is determined by the rate at which the stomach empties; faster emptying results in a greater fall in blood pressure. In the past both slow stomach emptying and symptoms were assumed to result from irreversible nerve damage, however it is now recognised that the blood glucose level itself has a reversible effect on both stomach contractions and symptoms. Our group has been the recipient of ongoing support from the NH and MRC for approximately 15 years to conduct research in this area. As a result we have performed the most comprehensive studies to date and developed new methods to evaluate stomach function in people with diabetes, resulting in international recognition. The studies proposed in this current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less