Mechanisms Of Action Of Neurochemicals And Modulators In Human Intestine: Changes In Disease
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are two serious gastrointestinal disorders, for which no effective medical treatment is known. We will investigate the hypothesis that abnormalities in the nerve chemicals found in the gut contribute to the aetiology of these diseases. Our studies will examine the sites of action (receptors) for these chemicals (neurotensin and acetylcholine) in the small and large intestine. The mechanisms governing motility changes in r ....Inflammatory bowel disease (IBD) and idiopathic chronic constipation (ICC) are two serious gastrointestinal disorders, for which no effective medical treatment is known. We will investigate the hypothesis that abnormalities in the nerve chemicals found in the gut contribute to the aetiology of these diseases. Our studies will examine the sites of action (receptors) for these chemicals (neurotensin and acetylcholine) in the small and large intestine. The mechanisms governing motility changes in response to these chemicals have been well studied in animal intestine, but there is little detailed information from the human intestine. This study will provide insight into the mechanisms operating in the normal bowel, providing a base for comparing bowel obtained from patients with IBD or ICC. We will also study bowel removed at surgery for acute diverticular disease (DD), representing another type of inflammation. Studies on isolated segments of colon from ICC patients will determine whether the contractility of the muscle is abnormal in general or only with respect to the chemicals under investigation. Other studies will investigate the inflammatory processes occurring in the bowel and whether this differs in IBD. Our work will facilitate understanding of the function of the bowel in health and in gastrointestinal disorders and may lead to new medical treatments for IBD and ICC.Read moreRead less
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Impact Of Airway Wall Fibrosis On The Efficacy Of Anti-asthma Drugs
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Most episodes of asthma are controlled or prevented by current medications. In a small, but significant proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in structure. These changes involve an increase in the amount of collagen (part of the cement between cells) making the airway stiffer. In this project, we are exploring the impact of the s ....Most episodes of asthma are controlled or prevented by current medications. In a small, but significant proportion of asthmatics (5-10%) symptoms persist despite the use of the best combinations of anti-asthma drugs. One of the reasons that acute episodes of asthma occur is that the airway tubes slowly change in structure. These changes involve an increase in the amount of collagen (part of the cement between cells) making the airway stiffer. In this project, we are exploring the impact of the stiffening of the airway on the way that different cells within the airway wall respond to drugs used to treat asthma. Our initial findings suggest that when the airway wall becomes stiffer with more collagen, there is a diminished benefit from the anti-asthma drugs. This new study is designed to identify the molecular mechanisms for the poor response to the anti-asthma drugs. With this knowledge it will be easier to design and test new drugs that are more effective in severe asthma.Read moreRead less
A group of nerves, called sensory nerves, supply most body organs including the uterus, and are well known to transmit information to the brain. It is now known that these nerves are also capable of releasing the chemicals (neuropeptides) from their endings within these body organs to affect their function. In the uterus these chemicals cause the uterus to contract. We have shown that neuropeptides known as tachykinins are effective in lower concentrations when applied to small specimens of uter ....A group of nerves, called sensory nerves, supply most body organs including the uterus, and are well known to transmit information to the brain. It is now known that these nerves are also capable of releasing the chemicals (neuropeptides) from their endings within these body organs to affect their function. In the uterus these chemicals cause the uterus to contract. We have shown that neuropeptides known as tachykinins are effective in lower concentrations when applied to small specimens of uterine tissue taken from non-pregnant women at hysterectomy than when applied to similar uterine specimens taken from pregnant women at caesarean section. The aim of this project is twofold. Firstly, we want to know why the tachykinins are more potent in uterine tissue from non-pregnant women. Possible explanations that we will examine are that tissues from non-pregnant women contain more sites of action at which the peptides can act, or alternatively, that there is decreased breakdown of these tachykinins in uterine tissue from non-pregnant women. This could occur if a substance known to break down the tachykinins in the uterus shows greater activity during pregancy than when a woman is not pregnant. Secondly, we wish to find out if other chemicals (substances that can produce inflammatory responses, and in particular a group of chemicals known as prostaglandins), that are known to be present in greater amounts in the tissues of women during disease states such as dysmenorrhoea, can cause the release of the neuropeptides that we are studying. If they do cause such a release of tachykinins, this could be an important factor contributing to the disease state. Our hypothesis is that tachykinins and the substances which can break them down may play an important role in regulating uterine contractility in non-pregnant and to a lesser degree in pregnant women.Read moreRead less
Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune ....Many serious inflammatory diseases, such as arthritis, septic shock, lung shock and heart disease are poorly controlled with currently available drugs. There is much evidence that a circulating hormone system called complement is involved with exacerbating these diseases, yet there are no drugs available to counteract its effects. One powerful component of the complement system, called C5a, causes inflammation and is suspected of causing tissue damage and suffering in these and many other immune diseases. An agent that could block the effects of C5a could be very useful clinically. There is no such drug available as yet. We have developed powerful agents which specifically block C5a in laboratory tests on isolated cells and tissues, and now propose to test their effectiveness in rats in which the above human disease conditions are mimicked. Our preliminary results are very promising, and we will conduct further testing to determine the scope of the actions of the new drugs. One of our new agents is orally active in rats, and we will determine how the blood levels of the drug relate to its beneficial effects. We are also planning to develop agents that are more effective when given by mouth. The results could lead to a new type of anti-inflammatory drug for humans suffering from a variety of diseases that are poorly treatable at present.Read moreRead less
Potential Roles Of 5-hydroxytryptamine In Diseases Affecting The Colon
Funder
National Health and Medical Research Council
Funding Amount
$346,018.00
Summary
The overall aim of this project is to examine the biological roles played by 5-hydroxytryptamine (5-HT) in the human colon. 5-HT is a naturally occurring substance of the body, normally involved in controlling many body activities. Relevance is placed in this project on the possibility that 5-HT is involved in causing or contributing to certain clinical conditions, either by excess or deficiency. The conditions that are the focus of this project are chronic constipation, diverticular disease and ....The overall aim of this project is to examine the biological roles played by 5-hydroxytryptamine (5-HT) in the human colon. 5-HT is a naturally occurring substance of the body, normally involved in controlling many body activities. Relevance is placed in this project on the possibility that 5-HT is involved in causing or contributing to certain clinical conditions, either by excess or deficiency. The conditions that are the focus of this project are chronic constipation, diverticular disease and irritable bowel syndrome. It is a matter of concern that there are no specific treatments for these conditions to date, hence the thrust of the project is to increase knowledge in this area, so hopefully treatments will be developed. Our Pharmacology research group is recognised for its experience in defining drug effects on the intestine and in characterising the target sites on which they act. This has been achieved by using an integrated approach whereby different functional methods reliably detect effects at the levels of the muscle layers, the nerves that supply them and at the absorptive surface using experimental animals. In addition, the use of isolated pieces of human colon obtained from discarded operation material has been an invaluable inclusion into this process. This has allowed us to establish that 5-HT has a target site in the muscle of the colon and that this leads to relaxation and inhibition of the normal spontaneous contractile activity, said anecdotally to be abnormally high in patients with irritable bowel syndrome. We now wish to apply this expertise and knowledge to test whether 5-HT is involved in causing chronic constipation and diverticular disease and to design a drug that would be expected to be of value in treating patients with irritable bowel syndrome.Read moreRead less
The In Vivo And In Vitro Biology Of The Novel Intracellular Ion Channel CLIC1 (NCC27)
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Ion channels are complex proteins that regulate the transports of salts, and essential cell function. We have recently cloned a new ion channel, CLIC1, unique in its location on the nuclear membrane as well as other sites. The function of this channel is uncertain, although we have suggested its association with cell growth and inflammation. We propose to investigate the function of CLIC1, dominantly based on gene knockout animals, in which the CLIC1 gene has been deleted.