Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
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 lining cells. We will employ a number of strategies to establish molecularly the exte ....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 lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
The Contribution Of Gp130-Stat3 During Wnt-beta-catenin Induced Intestinal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$396,275.00
Summary
There is growing evidence that cancer is initiated and develops not by the deregulation of a single gene or signaling pathway, but by multiple events. We will study the co-operation between two pathways - gp130-Stat and Wnt. These signaling pathways are frequently deregulated in many types of cancer, however their interaction remains poorly understood. We shall explore their mechanism of interaction during intestinal cancer in order to develop a novel therapeutic target for this disease.
New Mechanisms Of Immunomodulation By Interferon Transsignaling
Funder
National Health and Medical Research Council
Funding Amount
$540,441.00
Summary
The aim of this project is to characterise a new discovery of how the body can regulate its response to disease such as infections and cancer. Interferons are produced by the body to stimulate immune reactions to these diseases. We have dicovered that a circulating form of an interferon binding protein or receptor can change the nature of an immune response. We plan to study how this is achieved and whether this information can be used therapeutically.
Regulating Interferon Signalling In Innate Immunity
Funder
National Health and Medical Research Council
Funding Amount
$547,428.00
Summary
Our innate immune system evolved as the front line defence against infection. However an uncontrolled response can lead to serious diseases such as septic shock, chronic inflammation as in hepatitis, autoimmune diseases such as systemic lupus erythematosus. The immune respnse is regulated by important hormones such as interferon produced by the body in these situations. This project aims to understand the negative or inhibitory mechanisms that prevent dangerous side effects of interferons withou ....Our innate immune system evolved as the front line defence against infection. However an uncontrolled response can lead to serious diseases such as septic shock, chronic inflammation as in hepatitis, autoimmune diseases such as systemic lupus erythematosus. The immune respnse is regulated by important hormones such as interferon produced by the body in these situations. This project aims to understand the negative or inhibitory mechanisms that prevent dangerous side effects of interferons without restricting their postive or beneficial effects. We will examine the actions of a molecule called the Suppressor of cytokin Signaling 1 (socs1) which we have recently discovered to modulate the actions of interferon in the mouse. Initially our studies will determine which molecules SOCS1 binds to inside a cell and the consequences for cell activation pathways. The next step will be to specifically block this interaction in the mouse and determine the effects on models of viral infection and inflammatory disease. The outcome of these studies will be a better understanding of how the body fights disease via the immune response and potential new approaches to develop therapeutic drugs.Read moreRead less
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
An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an ....An obesity epidemic is evident in first world countries including Australia. Twenty seven percent of men aged 55-64 in this country are obese. Obesity results in increased mortality and morbidity from type 2 diabetes, cardiovascular disease, renal disease and endometrial cancer, among others. Given our flaccid lifestyles, it is imperative that the metabolic processes underlying obesity be fully understood, to allow development of suitable treatment modalities. This proposal seeks to establish an important new element in our understanding of the development of obesity, the transcription factor STAT5. With previous NHMRC support, we developed sophisticated genetically modified mice which lack defined signalling processes initiated by growth hormone, an anti-obesity agent. These studies showed a strong correlation between ability to activate STAT5 and resistance to obesity. There is fragmentary literature evidence to support our hypothesis, which could also explain some of leptins anti-obesity actions. Using mice which lack STAT5, we shall establish a role for STAT5 as an antiobesity agent. The actions of STAT5 are normally blocked by feedback inhibitors referred to as SOCS, discovered by Australians. We shall define which SOCS is the feedback regulator for obesity control, allowing us to develop specific anti-SOCS agents which will act as novel anti-obesity agents.Read moreRead less
Constitutive Activation Of The Growth Hormone Receptor
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
Growth hormone regulates growth, metabolism, bone, stem cells and longevity, and cancer. These actions are mediated by the GH receptor, and here we seek to understand how it is activated by the hormone through receptor constructs which are active without hormone, to different degrees. We will use these to elucidate its signaling properties, its ability to promote cancer, to grow muscle, and whether cases of giantism and cancer are a consequence of the activating mutations we have identified.
We propose to use a number of genetic approaches to identify key mutations involved in Polycythemia vera. We will analyse patient material, use cell lines and mouse models to investigate any new mutations. We also aim to dissect the role of an important blood cell surface receptor and its cooperation with the mutation in JAK2 recently shown to be important in this disease. These approaches will lead to better understanding of the disease and potential new diagnostic and drug strategies.
Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less