The Opposing Roles Of STAT1 And STAT3 Signalling By IL-6 Family Cytokines In Inflammation And Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly death of several thousand people in Australia alone. We have discovered a specific mutation in a gene for a receptor molecule called gp130 that results in the formation of stomach cancer in mice. Strikingly, mice with this mutation are also highly susceptible to clinically-relevant experimental models of septic shock and peritonitis, two chronic inflammatory disorders induced by bacterial ....Stomach cancer is the second most common cause of cancer-related deaths worldwide, and results in the yearly death of several thousand people in Australia alone. We have discovered a specific mutation in a gene for a receptor molecule called gp130 that results in the formation of stomach cancer in mice. Strikingly, mice with this mutation are also highly susceptible to clinically-relevant experimental models of septic shock and peritonitis, two chronic inflammatory disorders induced by bacterial infection. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of epithelial cells that line the stomach wall, as well as uncontrolled regulation of the immune system leading to local and systemic inflammation. At the molecular level, the mutation in gp130 leads to over-activation of two signalling molecules, Stat1 and Stat3, which are also used by a range of other receptors to transmit specific cellular responses. In the context of cancer and inflammation, Stat1 and Stat3 have opposing roles (ie Stat3 promotes cancer and can be both anti-pro-inflammatory, while Stat1 suppresses cancer and is pro-inflammatory), although as yet, the contribution of the gp130 receptor in directing Stat1 and Stat3 activation in these disorders is not known. Our proposal employs established strategies and unique mouse models to specifically address how the mutation in gp130 can orchestrate the opposing biological functions of these two molecules to drive stomach cancer and inflammation. The identification of mechanisms by which gp130-dependent activation of these two molecules causally relate to inflammation and stomach cancer will ultimately provide novel and rational approaches to target these molecules for the screening and treatment of various inflammatory disorders and cancers, including those of the stomach.Read moreRead less
In Vivo And Biochemical Appraisal Of Mitochondrial STAT3
Funder
National Health and Medical Research Council
Funding Amount
$421,747.00
Summary
The Signal Transducer and activator of transcription 3 (STAT3) protein is over-expressed or activated in most cancers. The paradigm for STAT3's role in cancer is that it drives the expression of genes which support tumour growth. Recently I found that STAT3 controls the altered metabolic state required for cancer progression, both by control gene expression and by entering the mitochondria. I propose define the mechanism of STAT3 mitochondrial activity and then translate these findings into anim ....The Signal Transducer and activator of transcription 3 (STAT3) protein is over-expressed or activated in most cancers. The paradigm for STAT3's role in cancer is that it drives the expression of genes which support tumour growth. Recently I found that STAT3 controls the altered metabolic state required for cancer progression, both by control gene expression and by entering the mitochondria. I propose define the mechanism of STAT3 mitochondrial activity and then translate these findings into animal models of cancer.Read moreRead less
The blood system is made up of different types of blood cells (red cells, white cells, platelets etc). The correct number of each type of cell is controlled by chemical messengers called cytokines. Because overactive cytokine signalling can lead to inflammatory disease and leukemia it is tightly controlled by the other molecules in the body. This project aims to determine the exact mechanism whereby this is achieved with the aim of developing therapies to treat inflammatory disease and leukemia.
Myeloproliferative diseases (MPD) and leukemias arise from blood cells with faulty molecular signalling caused by genetic mutations. We are studying MPD and leukemias that carry over-active versions of the JAK2 signalling molecule. We will use human and mouse leukemias and MPD to discover how these diseases develop, and how we can use specific medications to stop these processes. Our goal is to discover new, improved ways to treat leukemias and MPDs.
Identification Of Novel Targeted Therapies For JAK2-driven Leukemogenesis
Funder
National Health and Medical Research Council
Funding Amount
$392,717.00
Summary
Many leukemias are caused by particular signalling molecules becoming too active in blood cells. My research focusses on the molecules that are required by leukemic cells for their growth and survival. I will use mice that are prone to developing leukemia to study how these leukemias can be treated with drugs that block specific molecules. My goal is to discover new ways to treat leukemias that work better and have fewer side effects than current treatments.
Cytokine Signalling And The Regulation Of Normal And Leukaemic Blood Cells
Funder
National Health and Medical Research Council
Funding Amount
$948,684.00
Summary
The formation and actions of white blood cells are regulated by protein messengers called cytokines. Cytokines deliver their message by inducing the activation of signalling pathways that orchestrate the cell’s response to infection but when these responses occur too robustly or at inappropriate times they can lead to autoimmune disease, tissue damage and blood cancers. We study the naturally occurring feedback inhibitors of these processes in order to devise new treatments for these diseases.
Is Mitochondiral STAT3 Necessary For K-Ras Induced Myeloid Leukaemias?
Funder
National Health and Medical Research Council
Funding Amount
$425,326.00
Summary
Myeloid leukaemia (ML) is a family of diseases characterized by the expansion of white blood cells, leading to death from haematopoietic complications. One common mutation that gives a proliferative advantage in ML is in the Ras oncogenes. We recently showed that signal transducer and activator of transcription 3 (STAT3) is necessary for the transforming potential of Ras due to its ability to support the metabolic changes necessary for tumour growth. This research will characterize the STAT3-dep ....Myeloid leukaemia (ML) is a family of diseases characterized by the expansion of white blood cells, leading to death from haematopoietic complications. One common mutation that gives a proliferative advantage in ML is in the Ras oncogenes. We recently showed that signal transducer and activator of transcription 3 (STAT3) is necessary for the transforming potential of Ras due to its ability to support the metabolic changes necessary for tumour growth. This research will characterize the STAT3-dependent metabolic changes in ML.Read moreRead less
Colorectal cancer (CRC) is the 3rd most common cancer worldwide. 85% of CRC arises from mutations in the Wnt signalling pathway. We have shown that AZD1480, a drug that blocks Janus kinases (Jak) can prevent the appearance of Wnt mutant tumours and stop the growth of already established CRC in animal models. This project will test whether Jak inhibitors can improve treatment outcome and prolong disease free survival.
Controlling Neuroinflammation In Alzheimers Disease
Funder
National Health and Medical Research Council
Funding Amount
$639,577.00
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide, with 269,000 Australians currently diagnosed with AD and is expected to soar to about 981,000 by 2050. AD accounts for greater than 60% of all cases of dementia. This grant investigates the role that neuroinflammation plays in the progression and exacerbation of AD and will identify new therapeutic strategies to combat this insidious disease.