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.
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
Cell Surface Mucins In Gastrointestinal Mucosal Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$475,500.00
Summary
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. We have recently identified three of the seven genes currently known to produce this type of molecule. We propose that mucins have a very important role in maintaining the barrier between potentially infectious microorganisms often present in epithelial tracts and the internal organs. We also believe 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. We have recently identified three of the seven genes currently known to produce this type of molecule. We propose that mucins have a very important role in maintaining the barrier between potentially infectious microorganisms often present in epithelial tracts and the internal organs. We also believe that these molecules trigger epithelial cell defensive responses to the presence of microorganisms. The proposed research aims to prove these propositions and to elucidate the molecular mechanisms underlying function of cell surface mucins. Understanding the function of cell surface 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
Aldehyde-modified Antigens For The Immunotherapy Of Adenocarcinomas
Funder
National Health and Medical Research Council
Funding Amount
$284,250.00
Summary
The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a synthetic protein called mucin 1 (MUC1) which is exprssed on cells ....The incidence of breast cancer in women is 1 in 8 and the frequency of other cancers are rising. Even with conventional approaches such as surgery, cytotoxic therapy, radiotherapy and combination therapy only a few cancers are treatable. The development of a cancer vaccine will greatly benefit humanity similar to childhood and adult vaccinations for preventing infectious disease. In this proposal we intend to chemically modify a synthetic protein called mucin 1 (MUC1) which is exprssed on cells in breast cancer to make it more immunogenic - that is make it look more like a foreign protein so that the immune cells can make antibodies or killer cells that recognise it. These activated cells can now migrate to the tumour sites and kill the invading tumour. In order to do this we are going to introduce mannose, a particular sugar that can bind to important white blood cells and an aldehyde group that can activate immune cells. We will test the effectiveness of the modified proteins in mice to see if they can generate an good immune. If this is satisfactory then we will see if mice are vaccinated with these modified proteins can reject implanted mouse or human tumours. If these experiments are successful further work can be done with human cells and later clinical trials. Any methods developed here will be applicable to other cancers and also infectious diseases.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
Cell Surface Mucins In Gastrointestinal Infection And Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$591,967.00
Summary
Mucosal tissues, such as the gastrointestinal and respiratory tracts, are the most common site of infectious disease. We have found that the cells in these tissues produce molecules on their surface, known as mucins, that protect from infection. In the case of chronic infection the mucins prevent the inflammation that underlies the development of cancer. In this project we will be exploring the mechanisms by which mucins prevent infection and inflammation.
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.