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Exclusive Enteral Nutrition In Children With Crohns Disease
Funder
National Health and Medical Research Council
Funding Amount
$364,549.00
Summary
Crohn's disease occurs at any age, even in young children. One treatment for CD involves the use of a special drink (nutritional treatment). This works well for CD in children, helping to settle symptoms and heal the bowel surface. Despite being established as a treatment for 20 years, it is not yet clear how it works. These studies aim to work out how nutritional treatments work in CD. This should expand our knowledge about CD and may lead to further ways to prevent or manage CD.
Understanding The Role Of Infectious Agents As A Trigger Of Crohns Disease In Children With Early Onset Disease
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
Crohn's disease is a major cause of illness throughout the world. There is no cure and current therapies carry substantial risks. An infectious agent has been suggested as the trigger for disease but research has been inconclusive. Our study focuses on the characterisation of a novel virus we have identified that may trigger Crohn's disease in children at disease onset.
Role Of Protease Activated Receptors Type 2 (PAR2) During Inflammation Of Airways And Intestine
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in PAR2 is found in various diseases which are paralle ....Epithelial cells lining the airways and the intestine contain receptors that are activated by proteases, which are protein cleaving enzymes. Activation of the subtype 2 of these receptors (PAR2) has been shown to cause salt and water transport in intestinal cells in culture. Little is known about the effects of PAR2-activation in the native airways and intestinal tissues. These tissues will be studied in the present project. A large increase in PAR2 is found in various diseases which are paralleled by a strong inflammation. Thus, PAR2 is likely to play a central role in intestinal diseases such as acute infectious diarrhea and chronic inflammatory bowel disease. PAR2 may also participate in the severe diarrhea frequently observed in patients with intestinal tumors. Similarly, inflammatory mediators released during airway infections are likely to act on PAR2, causing inappropriate secretion and a running nose. Most importantly, PAR2 are found in large excess in the airways of asthma patients. Since nothing is known about the impact of these receptors on fluid and electrolyte transport in the airways it appears timely and highly relevant to study the function of PAR2 in the airway epithelium. We will assess PAR2 mediated responses in human nasal biopsies. A more detailed analysis of the intracellular processes will be done in mouse trachea. We will further study the function of PAR2 in the intestinal epithelium. Activation of the ion transport via PAR2 will be examined in the mouse distal colon and in human rectal biopsies. We will utilize techniques such as Ussing chamber and patch clamp recordings to analyze the transport processes. The results should gain new inside into the role of PAR2 during inflammatory diseases of the airways and the intestine such as asthma and chronic inflammatory bowel diseases.Read moreRead less
Investigation Of The Role Of Specific Mucous Associated Bacteria In Children And Young Adults With Crohns Disease
Funder
National Health and Medical Research Council
Funding Amount
$431,764.00
Summary
The role of bacteria in Crohn's disease is well accepted however to date no conclusive agents have been identified. Recent animal studies have implicated mucus-associated bacteria. We have recently shown that such bacteria, the Helicobacteriaceae, are present in humans and children with Crohn's disease. The aim of this project is to determine in children and young adults the role of these bacteria in IBD thus providing information that could be used to design improved therapies for IBD.
Identification And Characterisation Of The Genes And Pathways In Susceptibility To Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$575,581.00
Summary
One of the greatest challenges facing contemporary genetics is to understand the genetics of complex diseases such as inflammatory bowel disease, mutiple sclerosis and schizophrenia. This application seeks to unravel the complex interactions between susceptibility genes and environmental triggers that work together to produce the inflammatory bowel diseases (IBD). Current estimates of the prevalence and incidence suggests that there may be 30-40,000 Australians who suffer from these chronic debi ....One of the greatest challenges facing contemporary genetics is to understand the genetics of complex diseases such as inflammatory bowel disease, mutiple sclerosis and schizophrenia. This application seeks to unravel the complex interactions between susceptibility genes and environmental triggers that work together to produce the inflammatory bowel diseases (IBD). Current estimates of the prevalence and incidence suggests that there may be 30-40,000 Australians who suffer from these chronic debiltating set of diseases known separately as Crohn's disease and ulcerative colitis. One susceptibility gene for Crohn's disease has been recently been identified and the project outlined will extend our knowledge not only to the susceptibility genes themselves, but also to the genes that interact with them to produce the disease via a cascade of immune and inflammatory events. This work is part of a large international effort to identify all IBD susceptibility genes and builds on the resources of the Australian IBD Familiy Register- an Australia wide register of families in which multiple members are affected by CD or UC. A traditional gene mapping approach is used in concert with mutiple analyses of different gene expression profiles in disease versus normal bowel tissues as well as in cell lines from patients versus controls. Validation studies include identification of the particular tissues and cell types that are involved in the pathological immune response typical of IBD as well as characterisation of specific patient genotypes and- or phenotypes that may correlate with expression profiles. Results obtained will be used to identify genes underlying IBD susceptibility, the mutations that drive the disease and eventually therapeutic targets for modulation and treatment of disease.Read moreRead less
Inflammatory Bowel Disease (IBD) has two clinical forms known as Ulcerative Colitis (UC) and Crohn's Disease (CD). These are severe diseases which predominantly affect young people. They are occasionally fatal and often severely debilitating. Treatment of UC frequently requires removal of the large bowel and life long wearing of an ileostomy bag. While this is curative, its psychological and life style effects are very disturbing particularly in the young. The cause of IBD is unknown, although i ....Inflammatory Bowel Disease (IBD) has two clinical forms known as Ulcerative Colitis (UC) and Crohn's Disease (CD). These are severe diseases which predominantly affect young people. They are occasionally fatal and often severely debilitating. Treatment of UC frequently requires removal of the large bowel and life long wearing of an ileostomy bag. While this is curative, its psychological and life style effects are very disturbing particularly in the young. The cause of IBD is unknown, although it is clear that there are both genetic and environmental factors. We have developed a model of IBD in mice which appears to be very like human UC. We have generated genetically modified mice in which it appears that the mucous secreted by their bowel wall is different from normal. We propose to investigate how this change leads to UC. It appears likely that the mucous is defective and can not prevent some of the normal bacteria or other material present in the stools from entering the bowel wall and causing chronic inflammation. If we can show that this is the case, it adds strong support to the the idea that a similar genetic trait may occur in some humans and that this may be one of the genetic components which renders them susceptible to IBD. Put another way, it would be a pointer to the type of genetic defect which may underlie susceptibility in humans and so help to focus the search for the genetic component. Understanding genetic factors underlying disease susceptibility is vitally important to inform genetic counselling. In addition, understanding the various factors which lead to IBD is critical to developing rational treatments which target cause rather than the symptoms of the disease.Read moreRead less
Factors Controlling Leucocyte Migration In Healthy Intestine And In Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$195,217.00
Summary
Inflammatory bowel diseases (IBD) are relapsing and remitting disorders of the intestine that create substantial disability in a relatively young population of patients. Our treatments for these conditions have changed little in the last 30 years and they are commonly accompanied by side effects. Research into the mechanisms controlling the gut inflammation offers promise for the development of novel, targeted and less toxic therapies. The major mediators of damage in IBD are white blood cells r ....Inflammatory bowel diseases (IBD) are relapsing and remitting disorders of the intestine that create substantial disability in a relatively young population of patients. Our treatments for these conditions have changed little in the last 30 years and they are commonly accompanied by side effects. Research into the mechanisms controlling the gut inflammation offers promise for the development of novel, targeted and less toxic therapies. The major mediators of damage in IBD are white blood cells recruited from the circulation to affected intestine. This recruitment is induced by the production in damaged intestine of chemokines, proteins of the immune system that attract and activate white blood cells. Chemokines act through chemokine receptors on the surface of white blood cells, and earlier research by our group has demonstrated that these chemokine receptors can be functionally modulated by neuropeptides, proteins unrelated to chemokines that normally transmit messages within the nervous system. This project aims to explore the chemokines and chemokine receptors responsible for the recruitment of white blood cells to normal and IBD-affected intestine, in order to determine therapeutic targets for novel treatments. Moreover, the role of neuropeptides in modulating the recruitment of white blood cells to the intestine will be examined in cells from the human intestine, both normal and IBD-affected, as well as in an animal model of IBD. This project will provide an understanding of the signals responsible for the attraction of damaging white blood cells to sites of inflammation in the bowel and will indicate mechanisms used by the immune system to regulate those signals. It has the potential to direct us to new therapies that use highly targeted and physiologically appropriate approaches to controlling white blood cell trafficking in health and disease.Read moreRead less
Fine Scale Mapping And Identification Of The IBD1 Gene On Chromsosome 16
Funder
National Health and Medical Research Council
Funding Amount
$483,849.00
Summary
One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases (IBD). Studies on the prevalence, incidence and cost of IBD indicate that these diseases have considerable impact in Australia. On average, patients lose more than 13 days from work each year, and in hospital, IBD in-patients accounted for 7% of total admissions and 10% of total bed days at an average cost of $2600 per admission. We estimate that there may be more th ....One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases (IBD). Studies on the prevalence, incidence and cost of IBD indicate that these diseases have considerable impact in Australia. On average, patients lose more than 13 days from work each year, and in hospital, IBD in-patients accounted for 7% of total admissions and 10% of total bed days at an average cost of $2600 per admission. We estimate that there may be more than 10,000 Australians who suffer from IBD. The existence of a genetic predisposition to IBD is now well established, and there is strong evidence that the disease is complex, resulting from the interaction of a number of different genes. To date, one genetic localisation on chromosome 16 has been established in several different populations, and we have confirmed the importance of this localisation in the Australian population. We will further refine the localisation by fine scale mapping in the pericentromeric region of chromosome 16 by identifying and studying the inheritance of novel markers in the region. We will then identify and characterise the gene itself using several complementary appoaches that rely on differences at the molecular level between disease and normal tissue. This work is part of the international effort to identify all IBD susceptibility genes. Once that is achieved, approaches to explaining the interactions between the genes, their protein products and environmental triggers can be determined. Only when the mechanisms of these interactions are understood will the expectation of rational therapies based on an understanding of disease aetiology be possible.Read moreRead less
Characterisation Of A New Localisation For Susceptibility To Inflammatory Bowel Disease On Chromosome 12
Funder
National Health and Medical Research Council
Funding Amount
$76,125.00
Summary
One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases in order to develop more effective therapies. Although there have been advances in treatment over the last few years, the causes of IBD are still not known. The existence of a genetic predisposition to IBD is now well established, and there is strong evidence that the disease is the result of the interaction of a number of different genes. To date, two genetic locali ....One of the greatest challenges facing contemporary gastroenterology is to understand the causes of the inflammatory bowel diseases in order to develop more effective therapies. Although there have been advances in treatment over the last few years, the causes of IBD are still not known. The existence of a genetic predisposition to IBD is now well established, and there is strong evidence that the disease is the result of the interaction of a number of different genes. To date, two genetic localisations (one on chromosome 16 and a second on chromosome 12) have been confirmed in multicentre studies. We have identified a novel localisation for disease susceptibility on chromosome 12 in the Australian population during the course of a genome scan on 73 multiplex inflammatory bowel disease families. (The importance of this localisation has been confirmed in English and American families.) This localisation is quite separate from that originally described and many genes separate the two localisations. We will refine the new localisation by fine scale mapping in the region of the localisation that we originally identified in pure Crohn's disease families. At this stage, the localisation appears not to be important in families suffering from ulcerative colitis or in families in which both CD and UC occurs (known as mixed families), though this finding will be tested. Using state of the art molecular genetics, we will then identify and characterise the gene involved. The significance of this project lies in the importance of this localisation to the understanding of underlying biochemistry and genetics of a complex disease in which multiple genes are segregating and interacting in, some as yet undefined manner.Read moreRead less