Investigation Of Pancreatic Insulin-secreting Cell Function And Survival
Funder
National Health and Medical Research Council
Funding Amount
$375,750.00
Summary
Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes is eventually due to pancreatic insulin-producing beta-cell destruction, which is caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the cells. Thus, attempting to protect beta-cells against death and rescue their insulin secretory function is emerging as a strategy for the treatment of diabetes. However, how the beta-cells undergo death and how to protect the cell death are still n ....Diabetes remains a major health problem in Australia. Both type 1 and type 2 diabetes is eventually due to pancreatic insulin-producing beta-cell destruction, which is caused mainly by the cell death, so called 'apoptosis' or programmed suicide of the cells. Thus, attempting to protect beta-cells against death and rescue their insulin secretory function is emerging as a strategy for the treatment of diabetes. However, how the beta-cells undergo death and how to protect the cell death are still not completely understood. We have recently discovered a new protein, named sphingosine kinase, that is a strong protector against cell death. We also found that this enzyme is involved in process of insulin secretion. Thus, this application seeks to establish a dual role of this enzyme in protecting beta-cells from death and promoting insulin secretion by the cells. This will ultimately allow us to create new therapeutic strategy to target this protein for the management of diabetes.Read moreRead less
The Nuclear Growth Hormone Receptor- Its Actions And Mechanism Of Nuclear Translocation
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourog ....We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.Read moreRead less
Ceramide Metabolism And ER Stress In Fatty-acid Mediated Destruction Of Pancreatic Beta Cells
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
The underlying cause of Type 2 diabetes is the failure of pancreatic beta cells to secrete sufficient insulin to overcome the insulin resistance that is associated with obesity. Beta cell failre is associated with both defective insulin secretion and loss of beta cell mass. This proposal focuses on the cellular mechanisms and stress pathways whereby too much fatty acid promotes beta cell death.