Distribution, Pharmacology, Molecular Identity And Roles Of Purine Receptors In Enteric Neurons
Funder
National Health and Medical Research Council
Funding Amount
$395,250.00
Summary
Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion an ....Digestive function needs to be adapted to the great variety of foods that we eat, and to our variable dietary habits. Adaptation is controlled through an extensive nervous system in the wall of the gastrointestinal tract, the enteric nervous system, and through digestive system hormones. The enteric nervous system detects the volume and key chemical components in the gastrointestinal lumen and, through an integrating nerve circuitry, causes changes in the patterns of movement, fluid secretion and local blood flow. Digestive system diseases, for example irritable bowel syndrome, can involve disordered function of the enteric nervous system, and there is considerable research and development focus to identify drug targets in the enteric nervous system that can be used in therapy. Amongst potential targets are receptors for purines that are located on enteric neurons and are one of the important classes of receptor that is involved in communication between the neurons. These studies aim to identify the purine receptors, their roles in controlling digestive function and their potential as therapeutic targets in the treatment of digestive disease.Read moreRead less
Inosine-5' Monophosphate Dehydrogenase (IMPDH) is an enzyme responsible for providing a form of energy to cells, so that they may undertake their correct functions. Recently, we have demonstrated that IMPDH also has a role in the formation of fat droplets within cells, when they are exposed to excessive nutrients. In mammals, excess consumed energy is stored as fat droplets within all cells. In fat cells, the energy is stored in very large droplets, and we see this as extra body fat. This is som ....Inosine-5' Monophosphate Dehydrogenase (IMPDH) is an enzyme responsible for providing a form of energy to cells, so that they may undertake their correct functions. Recently, we have demonstrated that IMPDH also has a role in the formation of fat droplets within cells, when they are exposed to excessive nutrients. In mammals, excess consumed energy is stored as fat droplets within all cells. In fat cells, the energy is stored in very large droplets, and we see this as extra body fat. This is sometimes associated with an alteration in the hormone production of the cells, leading to problems such as diabetes. In other cells, the excess energy is stored as tiny fat droplets (lipid bodies) that can adversely affect the function of the cell. We have shown that blocking the action of IMPDH can interfere with the accumulation of fat in both fat cells and other types of cell. This suggests that IMPDH has an important role in the development of obesity and associated problems such as diabetes. In this study we aim to investigate in detail the role of IMPDH in the accumulation of fat droplets in cells. We will do this by looking at the effects of different forms of IMPDH in different cell types, including human fat cells. We will also study cells and animals with increased or decreased amounts of IMPDH, and investigate the effects of this on the development of increased fat stores and insulin resistance. These studies will increase our understanding of the role of IMPDH in the development of obesity, and may lead to identification of new avenues of treatment for obesity and type 2 diabetes.Read moreRead less
Virtual Screening In Structure-Based Drug Design For Malaria
Funder
National Health and Medical Research Council
Funding Amount
$285,000.00
Summary
Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat t ....Malaria continues to be one of the most serious health problems in the world today with approximately 300 million people affected and 1.5 million recorded deaths per year. The most deadly and widespread parasite responsible for this disease is Plasmodium falciparum. Because of the parasite's increasing resistance to traditional medication, there is an urgent need to develop more effective treatments. Two approaches are feasible: vaccines and new drugs. Both will probably be necessary to combat the spread and consequences of malaria. We are approaching this problem by targeting an enzyme which is essential for the survival of the parasite. All protozoan parasites make their purine nucleotides (the building blocks of DNA and RNA) by purine base salvage. Unlike humans, they cannot make purines from simple precursor molecules. The key enzyme in the salvage pathway is hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT). Our plan is to capitalize on knowledge of the precise structure of HGXPRT and the increased power of computers to determine which chemicals are able to bind tightly and specifically to the active site of the enzyme. We will then test the ability of these compounds to inhibit purified human and Plasmodium enzymes and their ability to inhibit the growth of the malarial parasite in red cells. Chemical synthesis will be used to improve the effectiveness of these compounds.Read moreRead less