Bile Acid Detoxification By Nuclear Receptor-mediated CYP3A Regulation
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that many of these adverse effects of obstructed bile flow are due to the retention of a component of bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic ....Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that many of these adverse effects of obstructed bile flow are due to the retention of a component of bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic and cause the death of cells in the liver if their concentration becomes too high. Evidence has emerged that the body has control mechanisms to try and combat rising levels of bile acids in cholestatic liver diseases. One such mechanism, which is the subject of this application, is the metabolism of bile acids to less toxic forms, by a process called hydroxylation. A particular class of liver enzymes, known as cytochromes P450 CYP3As, appear to mediate these hydroxylation reactions. Liver cytochrome P450 enzymes are important to medicine in areas as broad as drug breakdown, steroid hormone regulation and the formation or elimination of cancer causing chemicals. These enzymes are present in high concentration in the human liver, but the factors governing how much of these enzymes are produced have been poorly understood. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3As are increased by some drugs. We intend to determine the mechanism by which bile acids increase the level of CYP3A enzymes are how effective these enzymes are in hydroxylating bile acids. An understanding of these issues will allow us to better manage patents with cholestatic liver diseases and develop new strategies for treating these diseases, for example, development of novel drugs that increase bile acid hydroxylation in the liver.Read moreRead less
Molecular Mechanisms Of Feed-forward Regulation Of Bile Acid Detoxification And Elimination In Cholestasis
Funder
National Health and Medical Research Council
Funding Amount
$334,500.00
Summary
Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that may of these adverse effects of obstructed bile flow are due to the retention of a component or bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic ....Liver diseases in which there is obstruction to bile flow (cholestatic liver diseases) can lead to liver failure, liver cirrhosis as well as a diminished quality of life. Patients suffer from severe itching which may prove difficult to control. It is thought that may of these adverse effects of obstructed bile flow are due to the retention of a component or bile, called bile acids, within the body. Bile acids are detergent-like compounds formed from cholesterol. Some bile acids are highly toxic and cause the death of cells within the liver if their concentration becomes too high. Evidence has emerged that the body has control mechanisms to try and combat rising levels of bile acids in cholestatic liver diseases. These control mechanisms are complex and include enzymes from the cytochrome P450 family as well as several specialized transport molecules. In cholestasis these mechanisms promote the removal of bile acids through the urine as well as converting very toxic bile acids to less toxic forms. The present projects builds on discoveries concerning the regulation of cytochrome P450 enzymes made by our group over the last few years, including an in-depth understanding of the way the production of CYP3As is increased by some drugs. We intend to determine in detail how defense mechanisms against toxic bile acids are engaged. In particular, we wish to identify the receptor molecules that 'sense' the rising levels of bile acids that occur in cholestatic liver diseases. An understanding of these issues will allow us to better manage patents with these diseases and develop new strategies for treating cholestatic disorders, for example, development of novel drugs that can influence bile acid detoxification in the liver and other organs.Read moreRead less
Colon cancer causes about 4,000 deaths per year in Australia. A better understanding of the biology of colon cancer will lead to new therapeutics that will aim to overcome the treatment resistance. This project is focused on understanding how a novel protein SLIRP regulates colon cancer growth, and will investigate the mechanisms for its protective effects on the disease. If successful, these studies could provide the foundation for targeting SLIRP for therapeutics.
Function Of The Vitamin D Receptor In Hepatic Non-Parenchymal Cells
Funder
National Health and Medical Research Council
Funding Amount
$509,304.00
Summary
Nuclear receptors are sensors that control many aspects of metabolism, including responses to injury. Our work and has suggested that the Vitamin D Receptor (VDR) may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and in which cells VDR has this role. This work will provide a basis for future treatments to improve or prevent severe liver diseases.
The Physiological And Pathological Role Of The Bile Acid Receptor TGR5 And Its Potential Targeting For The Treatment Of Intestinal Motility Disorders And Visceral Pain.
Funder
National Health and Medical Research Council
Funding Amount
$311,860.00
Summary
Defects in the secretion of bile into the intestine cause digestive diseases, and abnormal circulating levels of bile acids induce profound itch and abnormal pain sensation. This project examines whether a cell-surface receptor (TGR5) produced by intestinal and sensory neurons mediates actions of bile acids on intestinal functions and pain. The project aims to define mechanisms of digestive and sensory disorders and identify new therapies for constipation, diarrhoea, and pain.
Bile Acid And Neurosteroid Signaling To The Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$587,950.00
Summary
Defects in the secretion of bile into the intestine cause digestive diseases, and abnormal circulating levels of bile acids induce profound itch and abnormal pain sensation. This project examines whether a cell-surface receptor (TGR5) produced by intestinal and sensory neurons mediates actions of bile acids on intestinal functions, itch and pain. The project will define mechanisms of digestive and sensory disorders and identify new therapies for constipation, diarrhoea, itch and pain.
ERRgamma And Skeletal Muscle: Insights Into Lipid Utilization And Catabolism
Funder
National Health and Medical Research Council
Funding Amount
$357,936.00
Summary
The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the ....The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). ERRgamma receptors are abundantly expressed in skeletal muscle, a major mass periperal tissue that acconts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile, lipid metabolism and obesity. Understanding the functional role of the orphan ERR receptors in skeletal muscle in the context of inflammation, lipid and energy homeostasis is of paramount importance in further understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes and obesity. Identification of novel ERRgamma targets that regulate metabolism in a major mass peripheral tissue, and positively influence the risk factors for cardiovascular disease, provides platforms for potential therapeutic intervention. Cardiovascular disease is the foremost cause of global mortality, and was responsible for >15 million deaths in 2003.Read moreRead less
Mechanisms Underlying The Effects Of Retinoic Acid Receptor Gamma In Haemopoiesis And Bone Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$366,801.00
Summary
My recent studies have demonstrated that a model of vitamin A deficiency results in impaired blood cell production and contributes to a blood cell disorder that can progress to leukaemia. There are also reduced numbers of blood stem cells (which give rise to all blood cells) and bone (which helps to regulate blood cell production) in this mouse model. In these studies I seek to understand more on how vitamin A deficiency causes these defects, which may lead to better treatment of such diseases.
NR1 Nuclear Hormone Receptors, And Skeletal Muscle Metabolism: Insights Into Dyslipidemia And Metabolic Disease.
Funder
National Health and Medical Research Council
Funding Amount
$582,547.00
Summary
The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). Orphan NR1 receptors are abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeost ....The significance of Nuclear hormone receptors (NRs) in disease is underscored by the range of pharmacopoeia for the treatment of NR-associated disorders (e.g 16% of the top 100 drugs target NRs). Orphan NR1 receptors are abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for ~40% of total body weight, and energy expenditure. Muscle is the major site of glucose metabolism and, fatty acid oxidation. Furthermore, it is an important regulator of cholesterol homeostasis and HDL levels. Consequently, it has a significant role in insulin sensitivity, the blood lipid profile, lipid metabolism and obesity. Understanding the functional role of the orphan NR1 receptors in skeletal muscle in the context of inflammation, lipid and energy homeostasis is of paramount importance in further understanding the mechanistic basis of dyslipidemia, chronic inflammation, insulin sensitivity, diabetes and obesity. Identification of novel NR1 targets that regulate metabolism in a major mass peripheral tissue, and positively influence the risk factors for cardiovascular disease, provides platforms for potential therapeutic intervention. Cardiovascular disease is the foremost cause of global mortality, and was responsible for >15 million deaths in 2003.Read moreRead less