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
Understanding The Role Of Nociceptin In PMNL-mediated Inflammation In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
This work will study the role of a type of protein in white blood cell movement into tissues, a process called inflammation. The outcome of this work may lead to the development of molecules which control this movement of white blood cells more specifically than existing therapeutics. Such inhibitors would potentially be useful as anti-inflammatory agents in a range of human diseases.
C-myb Regulates Stem-progenitor Cell Cycle Entry In Colonic Crypts Providing Insights Into Colo-rectal Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
During a human's life time the colon or large bowel produced an extraordinary volume of cells. This requires almost unimaginable numbers of cell divisions. We are investigating the role of a gene (c-myb) that we propose is one of the key regulators of normal colon growth and function. It is expressed in the base of the functional unit of the colon called the colonic crypt. The base contains the stem cell population which give rise to all the crypt cells. We have generated and gathered a unique a ....During a human's life time the colon or large bowel produced an extraordinary volume of cells. This requires almost unimaginable numbers of cell divisions. We are investigating the role of a gene (c-myb) that we propose is one of the key regulators of normal colon growth and function. It is expressed in the base of the functional unit of the colon called the colonic crypt. The base contains the stem cell population which give rise to all the crypt cells. We have generated and gathered a unique and comprehensive set of mutant mice that have various degrees of dysfunction of the c-myb gene. We will study the colons of these mice to determine how c-myb regulates cell growth. We will also investigate these mice under stress conditions like that associated with cancer therapies like radiation treatment. Understanding such genes will improve the management of cancer patient how suffer gastro-intestinal side effects such as diarrhoea, perhaps hyper-proliferative disorders like inflammatory bowel disease and finally colon cancer where complete loss of cell growth is a feature.Read moreRead less
Mechanisms Of Action Of The Trefoil Peptides In Promoting Healing In Models Of Inflammatory Bowel Disease
Funder
National Health and Medical Research Council
Funding Amount
$365,270.00
Summary
Preliminary experiments from our laboratory have shown that members of a family of small proteins called trefoil peptides, found naturally in the stomach, intestine and colon, are able to shorten the healing time of ulcers and reduce inflammation, in an animal model of inflammatory bowel disease. Crohn's disease and ulcerative colitis together make up the human inflammatory bowel diseases, or IBD for short. They afflict many members of the community, are debilitating, expensive to treat, and cur ....Preliminary experiments from our laboratory have shown that members of a family of small proteins called trefoil peptides, found naturally in the stomach, intestine and colon, are able to shorten the healing time of ulcers and reduce inflammation, in an animal model of inflammatory bowel disease. Crohn's disease and ulcerative colitis together make up the human inflammatory bowel diseases, or IBD for short. They afflict many members of the community, are debilitating, expensive to treat, and current treatments like corticosteroids and suppressors of the immune system have unpleasant and health-threatening side effects. There are therefore good reasons for the development of new forms of therapy which will be better tolerated and which are specific in their actions. We believe that the trefoil peptides may be good candidates on which new treatments for inflammatory disease might be based. The studies outlined in this proposal will test the best route of administration, and how often to give trefoil peptides in order to relieve the symptoms of experimental IBD. In addition the effectiveness of the trefoils will be compared to other agents currently used in IBD treatment, or which are known to relieve inflammation or speed the healing of the ulcerated colon. We will also carry out experiments designed to work out the mechanisms by which the trefoils' healing effects are mediated, and finally we will characterise a new member of the trefoil peptide family which we have recently discovered.Read moreRead less