Role Of PAK1 In Colorectal Cancer Growth And Metastasis Regulated By Gastrins
Funder
National Health and Medical Research Council
Funding Amount
$460,070.00
Summary
Increased level of PAK1(a protein kinase) was associated with the progression of colorectal (large bowel) cancer (CRC). Gastrin peptides are growth factors responsible for CRC development. The objective of this project is to determine the role of PAK1 in the regulation of CRC growth and metastasis by gastrin peptides. We will use cell culture, animal models and clinical samples in the program. A successful outcome will lead to the development of new CRC therapies such as inhibitors of PAK1.
TGF-beta Receptor Type III In Normal And Malignant Liver Growth: Modulation Of TGF-beta Activity
Funder
National Health and Medical Research Council
Funding Amount
$361,527.00
Summary
The transforming growth factor-beta (TGF-beta) family is a group of multifunctional growth factors which regulates a number of important cellular functions, including proliferation, differentiation, and survival. Therefore, the proper functioning of this system is critical for the normal development and maintenance of most tissues. Dysregulation of this system is implicated in many pathological conditions, including cancer. The actions of TGF-beta are mediated by three cell surface proteins, ter ....The transforming growth factor-beta (TGF-beta) family is a group of multifunctional growth factors which regulates a number of important cellular functions, including proliferation, differentiation, and survival. Therefore, the proper functioning of this system is critical for the normal development and maintenance of most tissues. Dysregulation of this system is implicated in many pathological conditions, including cancer. The actions of TGF-beta are mediated by three cell surface proteins, termed the type I, II and III TGF-beta receptors. The type I and II receptors are required for transmitting the TGF-beta signal to the nucleus of the cell. Existing data suggest that the type III receptor is not required in TGF-beta signaling but is required for the regulation of TGF-beta levels at the cell surface. However, the function of this receptor and its role in TGF-beta mediated regulation of cell growth and survival is poorly understood. Our earlier work indicated that the TGF-beta type III receptor is particularly important for limiting TGF-beta activity during normal liver development. The currently proposed research will examine the effects of type III receptor deficiency on liver cells in the adult mouse in order to determine whether alterations in cell growth and survival occur in the absence of this receptor. Becauses TGF-beta is a key regulator of liver growth and altered levels of TGF-beta in liver have been demonstrated to lead to liver cancer in mice, we anticipate that targeting the deletion of the type III gene to liver cells will provide a system in which to study compromised regulation of cell growth. This work is therefore expected to yield information relevant to the role of this receptor in TGF-beta regulated processes in normal and cancerous growth. Because the type III receptor appears to control the level of TGF-beta activity, this work will allow further evaluation of the potential for therapeutic uses for type III receptor-like agents.Read moreRead less
Cholestasis And Hepatocyte Injury In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$615,967.00
Summary
The aim of this project is to understand the consequences of long-term cholestasis or impaired bile excretion/flow on normal liver cells (hepatocytes) and to test whether specific bile acids can cause irreversible damage to hepatocytes leading to their transformation into pre-malignant cells and hepatocellular carcinoma (primary liver cancer). The results from this project will inform new strategies in screening, prevention and treatment of liver cancer in children and adults with cholestasis.
Significance Of Microparticles In The Pathogenesis Of Liver Ischemia Reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
The overall aim of the project is to investigate the significance of microparticles in liver ischemia reperfusion injury (IRI). IRI causes damage to donor livers stored in preparation for liver transplantation. We postulate that microparticles released from the liver are critical in this form of injury. The expected outcomes are novel insights into liver IRI with the aim of developing new approaches to prevent liver damage during liver surgery, transplantation and shock.
The Role Of MBOAT7 In Hepatic Inflammation: Implications For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$848,340.00
Summary
When a fatty liver progresses to develop inflammation, patients are at-risk of liver-related morbidity and death. Currently, there are no effective therapies. From human studies, we have discovered that a lipid modifying enzyme (MBOAT7) profoundly regulates liver inflammation. In this proposal, we will obtain a detailed understanding of how the activity of this pathway modulates inflammation. We expect to show that MBOAT7 is a novel ‘druggable’ pathway for the treatment of liver inflammation.
P53 And Hepatocyte Proliferation In Chronic Liver Disease
Funder
National Health and Medical Research Council
Funding Amount
$331,360.00
Summary
The aim of this project is understand how loss of control of p53, a tumour suppressor gene, in liver cells causes the transformation of normal liver cell (hepatocyte) to ‘rouge’ pre-cancerous cells in hepatocellular carcinoma (HCC) or primary liver cancer. We will test novel therapies to restore p53 function in liver cells in order to prevent or retard the development of HCC in patients with cirrhosis and those ‘at risk’ of this rapidly increasing fatal cancer in Australia.
MERTK Receptor Tyrosine Kinase: A Novel Therapeutic Target For Liver Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$870,972.00
Summary
Hepatic fibrosis is the principal cause of liver-related morbidity and mortality, for which there are no effective therapies. Thus, there is an urgent and unmet need to identify new targets to treat liver fibrosis. We have demonstrated for the first time, that liver fibrosis correlates with elevated hepatic expression of MERTK, a receptor tyrosine kinase. This project will explore whether MERTK function can be exploited to target and reverse liver fibrosis
LIM KINASE 1 (LIMK1) AND METASTASIS, THE SEARCH FOR LIMK1 INHIBITORS
Funder
National Health and Medical Research Council
Funding Amount
$461,250.00
Summary
Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. Importantly, we have demonstrated that (1) inhibiting LIMK1 blocks the formation of metastatic ....Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. Importantly, we have demonstrated that (1) inhibiting LIMK1 blocks the formation of metastatic tumours in mice, and (2) introduction of this protein into tumour cells makes them more invasive. In addition, we find that the level of LIMK1 is much higher in human tumour cell lines that have the propensity to easily form tumours in mice. Also, measuring the level of this protein in cancer cells that spread to other organs shows that it is at significantly elevated levels when compared to normal tissue. The goals of this research are to: (1) understand whether the ability of LIMK1 to regulate tumour spreading and invasiveness correlates with its ability to control metastasis; (2) examine in human tumour samples whether the levels of LIMK1 correlate with the development of metastatic tumours; and (3) search for drugs that can inhibit the activity of this protein. The results from this research will be highly significant because LIMK1 levels are likely to be an important marker for which tumours will become metastatic. It is possible that, at the time of tumour diagnosis, LIMK1 measurements will enable the clinician to predict whether an individual tumour will become metastatic. Secondly, this protein is a novel drug development target. Drugs that inhibit this protein may block the ability of tumours to invade and metastasise.Read moreRead less
The Role Of The Hepatocyte And EMMPRIN In Liver Injury
Funder
National Health and Medical Research Council
Funding Amount
$607,487.00
Summary
This research plan investigates the role of the hepatocyte, the principal functional cell within the liver in the development of liver disease. Liver injury can result in end-stage scaring known as cirrhosis as well as leading to liver cancer. Our research aims to identify strategies for reversing the fibrotic process and result damage to the liver