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
ASSESSMENT OF ENDOPLASMIC RETICULUM STRESS AND MUTATIONS IN MUCIN OLIGOMERIZATION DOMAINS IN ULCERATIVE COLITIS
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
Ulcerative colitis affects 0.2% of Australians causing chronic or recurrent health morbidity and affecting employment. In severe cases it is life threatening. Its pathogenesis remains poorly understood. We have exciting and novel preliminary data from humans and informed by our unique animal models that make us propose that the disease is caused by Endoplasmic Reticulum Stress due to misfolding of mucin. We have designed fully powered prospective clinical and lab studies to test this hypothesis.
My basic science and translational research centres around elucidation of the function of the mucosal barrier in preventing infection, inflammation and development of cancers, and how defects in this barrier lead to these diseases.
We have generated mice with symptoms mirroring the inflammatory bowel disease, ulcerative colitis (UC). These mice have mutations in the gene producing the major component of the protective mucus layer in the intestine. The mutations lead to a phenomenon known as ER stress. We have shown that ER stress also occurs in UC, opening up a new understanding of this disease. The proposed research will explore links between ER stress and inflammation and test potential new treatments for UC.
Acute Severe Ulcerative Colitis - Clinical And Translational Studies
Funder
National Health and Medical Research Council
Funding Amount
$340,891.00
Summary
One in five patients with severe ulcerative colitis, a condition resulting in damage to the large bowel, may require surgery to remove the bowel. This project aims to find out how best to avoid surgery using a drug called infliximab which targets the immune system to reduce bowel damage. This study also aims to find changes in the immune system that cause ulcerative colitis and identify which patients are more likely to avoid surgery with infliximab thereby minimising side effects and costs.
Muc1 Regulation Of The NLRP3 Inflammasome In The Gastrointestinal Tract
Funder
National Health and Medical Research Council
Funding Amount
$444,351.00
Summary
The mucin Muc1 is an important part of the barrier against infection in the gut, and appears to protect against development of bacterial inflammatory disease. We have identified that Muc1 suppresses activation of the inflammasome (a mechanism by which pathogens cause inflammation). We will now examine how Muc1 does this and explore the importance of this effect on inflammatory disease in the intestine. This may identify novel approaches for protecting against gastric and colorectal cancer.
Recombinant Bacteria Expressing Oligosaccharide Receptor Mimics For Prevention Of Enteric Infections
Funder
National Health and Medical Research Council
Funding Amount
$451,056.00
Summary
Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant ....Gastrointestinal infectious diseases kill more than 3 million people each year. The principal microbial pathogens responsible for these infections are known to exploit oligosaccharides on the surface of host cells as receptors for ahesins or toxins. We have developed (and patented) a novel anti-infective strategy, based on mimicry of oligosaccharide receptors for toxins and adhesins produced by enteric pathogens on the surface of harmless carrier bacteria. Oral administration of such recombinant probiotics has the potential to prevent enteric infections by binding and neutralizing toxins in the gut lumen and by blocking adherence of the pathogen to intestinal epithelial cells. As a prototypic example, we have developed a bacterium capable of preventing the serious consequences of Shiga toxigenic Escherichia coli (STEC) infections; this agent binds Shiga toxin with very high efficiency and is 100% protective in animal models. The strategy has very broad applications, however, and receptors for virtually any pathogen can be mimicked by expression of appropriate glycosyl transferases in a suitable harmless host bacterium. This proposal involves extension of our existing work to develop therapeutic agents for other important life threatening diarrhoeal diseases including cholera, travellers' diarrhoea, dysentery, antibiotic-associated colitis, rotavirus, etc.Read moreRead less
Enhancing Control Of Enteric Bacteria Through Pathogen Genomics
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Bacteria part of the Enterobacteriaceae family are responsible for causing significant enteric disease in Australia and internationally. Compounding the public health threat posed by these enteric bacteria is the rise in antimicrobial resistance, which limits treatment options. This project has three complementary research objectives; 1) to investigate new control strategies; 2) to better understand outbreak dynamics and; 3) to explore how bacteria are causing new disease in humans.