Loss Of Cytostatic Regulation By TGF-beta During EGFR-driven Tumor Development
Funder
National Health and Medical Research Council
Funding Amount
$605,031.00
Summary
Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulato ....Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulators in tumour formation and as such they are potential therapeutic targets. However, while both pathways have been studied extensively, little is known about the cross-talk between the TGF-b and EGF pathways. This project will establish the generality of a new tumor signaling axis, namely EGFR-Stat3-Smad7-TGF-b in EGFR-overexpressing tumors. Practically, it will provide guidelines for the development of new approaches for treating effectively the EGFR-driven tumors.Read moreRead less
Specificity Of Smad Proteins In Transforming Growth Factor-beta Signaling
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
Transforming growth factor-betas (TGF-beta) regulate a fascinating array of cellular processes including cell proliferation, differentiation, migration, organization and death, as well as affect a wide range of biological functions, such as embryonic development, hematopoiesis and immune and inflammatory responses. Given the multifunctional nature of TGF-beta action, it is not surprising that the disruptions of TGF-beta functions have been implicated in many human disorders, particularly in colo ....Transforming growth factor-betas (TGF-beta) regulate a fascinating array of cellular processes including cell proliferation, differentiation, migration, organization and death, as well as affect a wide range of biological functions, such as embryonic development, hematopoiesis and immune and inflammatory responses. Given the multifunctional nature of TGF-beta action, it is not surprising that the disruptions of TGF-beta functions have been implicated in many human disorders, particularly in colorectal and pancreatic cancers. The Smad proteins (there are ten of them) are critical components of TGF-beta cellular actions. In fact, Smad4 also called DPC4 for deleted in pancreatic carcinoma locus 4. This project addresses how each Smad protein works at molecular level in the cell, and which part of biological functions it regulates. Collectively, the outcomes of the project may provide clear and specific molecular targets to treat TGF-beta related diseases such as colorectal and pancreatic cancers.Read moreRead less
The Role Of TGF-beta Signaling In Suppression Of Stat3-mediated Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$667,000.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach mining cells. Our proposal combines the expertise of the two investigators in signal ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach mining cells. Our proposal combines the expertise of the two investigators in signal transduction and the making of genetically modified mouse models. These strategies will be employed to specifically address in the laboratory mouse the function of two specififc signaling cascades, called Stat3 and TGF-beta. The identification of detailed description by which these molecules causally relate to cancer formation will provide clear and specific molecular targets for future therapies to treat various cancers, including those of the stomach.Read moreRead less
Differential Cooperation Of MAPKs With TGF-beta Signaling In Epithelial-Mesenchymal Transition
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identi ....Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identify key molecular and cellular mechanism controlling this switch, with the ultimate aim being to devise treatments that inhibit tumor metastasis. The results from this work will provide clear and specific targets to prevent and to treat tumor metastasis. More importantly, the success of strategies used in this work can potentially be used clinically for tumor treatment.Read moreRead less
A New Mechanism Of Tissue Fibrosis - A Small Peptide Regulator Of The TGF-beta1/Smad Pathway
Funder
National Health and Medical Research Council
Funding Amount
$768,757.00
Summary
Progressive scarring, or fibrosis, of organs leads to their loss of function. Fibrotic diseases are devastating to both the individual and our community and we lack effective therapies. We have identified a small protein, named SPRF, which represents a new mechanism in tissue fibrosis. These studies will examine the role of the SRPF protein in models of kidney, heart and lung fibrosis and its underlying mechanism of action. We will also test a therapy based on inhibiting SPRF function.
21,000 Australians receive kidney replacement therapy and many more die of kidney failure as a result of kidney fibrosis. TGF-?, a growth factor causing kidney fibrosis, is also anti-inflammatory and promotes healing. We aim to prove that targeting downstream messengers (Foxo/?-catenin) of TGF-? will prevent fibrosis while promoting TGF-?’s anti-inflammatory and healing actions. A successful outcome will lead to a novel cure for preventing kidney failure and failure of other organs.
The Role Of TGFB1 In The Pathophysiology Of Late Stage Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$612,961.00
Summary
Schizophrenia is triggered in people with a genetic predisposition by as yet unknown environmental factors. Having shown that changes in gene expression in the brains of people with schizophrenia vary as the disease progresses, this application seeks to understand the changes in a pathway regulated by transforming growth factor ?1 that occur late in the progression of the illness. Understanding the changes in this important pathway could affect how people with schizophrenia are treated as their ....Schizophrenia is triggered in people with a genetic predisposition by as yet unknown environmental factors. Having shown that changes in gene expression in the brains of people with schizophrenia vary as the disease progresses, this application seeks to understand the changes in a pathway regulated by transforming growth factor ?1 that occur late in the progression of the illness. Understanding the changes in this important pathway could affect how people with schizophrenia are treated as their disorder progresses.Read moreRead less
Therapeutic Potential Of Transforming Growth Factor-beta Proteins For The Diagnosis And Treatment Of Female Infertility
Funder
National Health and Medical Research Council
Funding Amount
$942,961.00
Summary
We discovered and manufactured a growth factor produced uniquely by the egg. We named this growth factor cumulin. It is a powerful regulator of ovarian function and egg quality. This project will study the basic mechanisms of how cumulin works in the ovary. We will then develop an assay to measure it as a biomarker of human egg quality and quantity. New approaches in fertility preservation for cancer survivors will be developed using cumulin.
Transforming Growth Factor Beta As A Causal Factor In Human Osteoarthritis
Funder
National Health and Medical Research Council
Funding Amount
$634,359.00
Summary
Osteoarthritis (OA) is a common painful degenerative disease of the joints, which constitutes a major and growing public health problem, and for which there are no effective therapies. Our exciting recent research in the mouse has found that TGFb over-activity in the bone has a critical causal role in OA pathogenesis. Because TGFb silencing in bone could provide an entirely new way to slow the progression of OA, we propose to investigate this pathway in human OA.
Differentiation Of Pro-fibrotic From Anti-inflammatory Effects Of TGF-? In Kidney Fibrosis By Targeting ?-catenin
Funder
National Health and Medical Research Council
Funding Amount
$593,019.00
Summary
More than 2500 Australians commence kidney replacement therapy each year and many more die of kidney failure as a result of kidney fibrosis. TGF-?, a growth factor causing kidney fibrosis, is also anti-inflammatory. Our project aims to prove that targeting a downstream messenger (?-catenin) of TGF-? will prevent kidney fibrosis while leaving TGF-?’s anti-inflammatory actions untouched. A successful outcome will lead to a novel cure for preventing kidney fibrosis and fibrosis of other organs.