Regulation Of Cellular Responses To Neuropeptides.
Funder
National Health and Medical Research Council
Funding Amount
$83,510.00
Summary
Neuropeptides are chemicals released from nerves that are responsible for communication between the nerves, glands, muscles or other nerves. Neuropeptides exert their diverse biological effects by interacting with small structures on the cells they wish to communicate with. These structures bind the neuropeptide and are termed neuropeptide receptors. The responses of tissues to neuropeptides, for example, contraction of muscle, decrease with continued exposure to the neuropeptide. This reduction ....Neuropeptides are chemicals released from nerves that are responsible for communication between the nerves, glands, muscles or other nerves. Neuropeptides exert their diverse biological effects by interacting with small structures on the cells they wish to communicate with. These structures bind the neuropeptide and are termed neuropeptide receptors. The responses of tissues to neuropeptides, for example, contraction of muscle, decrease with continued exposure to the neuropeptide. This reduction in response is termed desensitization is thought to turn off the response to cells following stimulation by neuropeptides. In this study, I will investigate the mechanisms behind the desensitization of VPAC receptors which are a found throughout the body and have many important roles for example, gastrointestinal, pancreatic and reproductive function and control of muscle. VPAC receptors are also highly expressed in certain many cancers such as breast, prostate and colon carcinoma. The wide variety of functions that these receptors perform and the wide distribution in the body suggest that these are very important receptors. To date research into the responses and desensitisation of these receptors has been lacking, and the work that has been done has become confusing as more receptors and neuropeptides which bind them are discovered. The current project aims to carefully study these receptors and to determine their role in health and disease. The understanding the interaction of receptor and neuropeptide can perhaps lead to development of new therapeutic agents.Read moreRead less
Pancreatic Cancer is the fourth leading cause of cancer death in men and women in Western societies. Nothing, apart from surgery in a small proportion of individuals gives any hope. The identification of novel treatment strategies in the modern era necessitates a rational scientific approach, where an understanding of the molecular mechanisms involved in the evolution of cancer underpins the development of such strategies in an efficient manner. Retinoids are derivatives of Vitamin A, and have b ....Pancreatic Cancer is the fourth leading cause of cancer death in men and women in Western societies. Nothing, apart from surgery in a small proportion of individuals gives any hope. The identification of novel treatment strategies in the modern era necessitates a rational scientific approach, where an understanding of the molecular mechanisms involved in the evolution of cancer underpins the development of such strategies in an efficient manner. Retinoids are derivatives of Vitamin A, and have been used extremely successfully in the treatment of some leukaemias. Unfortunately, retinoids have not worked as well in other cancers. We have identified an important role for abnormal retinoid function in the evolution of pancreatic cancer, which may be responsible for the lack of effective response to retinoid treatment. This project focuses on identifying if these abnormalities in retinoid function can be reversed with adding specific pharmaceuticals so that retinoid based therapies will be effective in pancreatic cancer.Read moreRead less
Inflammation Drives TFF2 Epigenetic Silencing In Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$618,909.00
Summary
Over one million deaths from stomach cancer will occur annually in the next decade. This often fatal disease can be caused by infection from childhood by the bacterium H. pylori. We will study a new link between the inflammation caused by H. pylori and a type of mutation known as epigenetic silencing that switches off a gene which normally prevents stomach cancer. Understanding this process will help us to discover approaches for early detection of stomach cancer and lead to the development of n ....Over one million deaths from stomach cancer will occur annually in the next decade. This often fatal disease can be caused by infection from childhood by the bacterium H. pylori. We will study a new link between the inflammation caused by H. pylori and a type of mutation known as epigenetic silencing that switches off a gene which normally prevents stomach cancer. Understanding this process will help us to discover approaches for early detection of stomach cancer and lead to the development of new drugs that prevent disease.Read moreRead less
Chronic Gastrointestinal Symptoms And Diabetes Mellitus: Risk Factors And Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$271,527.00
Summary
Why many people with diabetes mellitus are afflicted by gastrointestinal (GI) symptoms remains uncertain. Irreversible damage to the nerves controlling the gut (autonomic neuropathy) is often considered to be important. An alternative cause of increased GI symptomatology in diabetics is poor glucose control. Some studies have shown that acute shifts in glucose levels induce changes in the gut relevant to the onset of GI symptoms. For example, high glucose levels acutely cause slower stomach empt ....Why many people with diabetes mellitus are afflicted by gastrointestinal (GI) symptoms remains uncertain. Irreversible damage to the nerves controlling the gut (autonomic neuropathy) is often considered to be important. An alternative cause of increased GI symptomatology in diabetics is poor glucose control. Some studies have shown that acute shifts in glucose levels induce changes in the gut relevant to the onset of GI symptoms. For example, high glucose levels acutely cause slower stomach emptying times, leading to feelings of fullness. Though the effects of chronic glucose levels are yet to be properly explored, population data show that poor control in the long-term is related to an increase in symptoms. The aim of this prospective study is to determine the roles played by both autonomic neuropathy and glucose control in the development of GI symptoms among diabetics. All past research has been cross-sectional, and so cannot tell us if one or both of these factors cause GI problems in diabetes. For example, it is possible that autonomic neuropathy causes an increase in GI symptoms such as nausea and fullness, which in turn induces poor glucose control though lack of appetite or inadequate stomach emptying. Upon study inclusion, all study participants will undergo a series of autonomic tests. At 3 month intervals for a period of 30 months, they will be asked to complete a 2-week diary card detailing their GI symptoms and glucose readings, and also supply blood and urine samples for analysis twice each year. Two years from the study outset, participants will again complete the autonomic test series. Psychiatric co-morbidity will be investigated using the Composite Diagnostic Interview (CIDI-Auto) at the autonomic testing time points. The study will be undertaken at the Gastroenterology Research Unit at Nepean Hospital, in collaboration with the Royal Adelaide Hospital, centres with proven track records in diabetes investigation.Read moreRead less
Epithelial cell surface mucins are large complex proteins found on the surface of all mucosal epithelial tissues, for example in the respiratory, gastrointestinal, reproductive and urinary tracts. Most bacterial and viral pathogens enter the body via mucosal tissues. We have recently demonstrated that mucin proteins are a vital component of initial defence against mucosal pathogens. Defects in these proteins probably predispose individuals to common chronic infective and inflammatory diseases. T ....Epithelial cell surface mucins are large complex proteins found on the surface of all mucosal epithelial tissues, for example in the respiratory, gastrointestinal, reproductive and urinary tracts. Most bacterial and viral pathogens enter the body via mucosal tissues. We have recently demonstrated that mucin proteins are a vital component of initial defence against mucosal pathogens. Defects in these proteins probably predispose individuals to common chronic infective and inflammatory diseases. The proposed research aims to explore the mechanims by which mucins protect from infection, with a focus on the gastrointestinal tract. Gastrointestinal infections remain one of the major causes of mortality in children in undeveloped countries. We believe that these proteins are a critical hereto unrecognised element of immunity and that the proposed studies will have broad significance for treatment and prevention of infection. Additionally, understanding the function of mucins could lead to the development of new drugs to treat epithelial inflammation such as that seen in inflammatory bowel diseases and respiratory diseases such as asthma and cystic fibrosis.Read moreRead less
Mechanisms Of Mechanotransduction In Primary Visceral Afferents
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Mechanotransduction is the process whereby mechanical stimuli are converted into signals in sensory nerves. This forms the basis of touch, hearing, position sense and many aspects of internal perception. It also constitutes a major component of pain. Our group aims to discover the molecular basis of mechanotransduction in mammals, and in particular how it relates to signaling of events in the digestive system. We and our collaborators have been among the first to explore this question, and have ....Mechanotransduction is the process whereby mechanical stimuli are converted into signals in sensory nerves. This forms the basis of touch, hearing, position sense and many aspects of internal perception. It also constitutes a major component of pain. Our group aims to discover the molecular basis of mechanotransduction in mammals, and in particular how it relates to signaling of events in the digestive system. We and our collaborators have been among the first to explore this question, and have found that three genes are responsible for many aspects of mechanotransduction. Each gene is transcribed to produce a channel or pore in the membrane of sensory nerve fibres which responds to mechanical forces by allowing ions to enter and induce electrical signals. Our early findings in mice with disruption of individual genes indicate that a complex positive and negative interaction of these channels must underlie normal mechanotransduction. However, these channels must represent only a part of the transduction mechanism, with extracellular and intracellular anchors inevitably playing a major role. The identity of such anchoring proteins in mammals is currently emerging, and we are fortunate to have access to mice deficient in specific genes that will provide information about candidates for this role. Through our studies on mechanotransduction in the digestive system in parallel with our collaborators' studies on mechanotransduction in skin we shall not only identify the fundamental mechanisms of mammalian mechanotransduction, but also reveal which components of mechanotransducers are peculiar to the gut. Such peculiarities provide molecular targets for therapy of diseases in which alteration of mechanosensory signaling is itself an aim.Read moreRead less
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.
Glucose is a critical fuel for living organisms and its presence in the gut triggers nerves that slow stomach emptying. However, little is known of how glucose is actually detected in the gut. We have established that sweet taste molecules of the tongue are also present in the gut, where they may detect glucose. This research will measure the expression and function of these molecules in the gut of humans and mice, and reveal key information on their potential as targets in health and disease.
Upper Gastrointestinal Motility And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$543,301.00
Summary
The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent complication of diabetes, may contribute to a number of problems including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. The blood glucose ....The application of novel techniques to evaluate gastrointestinal motor function has established that the rate at which the stomach empties is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying, which was thought to be an infrequent complication of diabetes, may contribute to a number of problems including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. The blood glucose level itself also has a reversible effect on both stomach contractions and symptoms; when the blood glucose is abnormally high, the rate at which the stomach empties is slower, and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of sugar from the intestine have a major influence on the rise in the blood glucose level after a meal. This is important because in people with diabetes it is desirable to maintain blood glucose levels as close as possible to normal to minimise the risk of complications such as eye and nerve damage. Specific modifications in diet and recently developed drugs which have actions similar to that of the hormone, glucagon-like peptide-1, may improve blood glucose control in type 2 diabetes by slowing the rate of gastric emptying. People with cystic fibrosis frequently develop diabetes which is often difficult to manage; this may result from abnormally rapid gastric emptying and impaired release of hormones. If so, pancreatic enzyme replacement, in the form of tablets, should prove effective. Our group has conducted research in this area for about 24 years and have performed the most comprehensive studies to date 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