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
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.
Control Of TGF-beta Superfamily Signalling In Human Disease
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
Members of the transforming growth factor ? (TGF-?) family of proteins play crucial roles in adult tissue homeostasis. In recent years a new paradigm has emerged suggesting that inhibition of TGF-? signalling could be an effective strategy for restoring homeostasis in disease-affected tissues. Dr Harrison’s overall research strategy is based on this concept, and is particularly focussed on developing specific antagonists of individual TGF-? proteins.
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.
Interactions Between IL-15 And TGF-beta Signalling Pathways Reveal Novel Therapeutic Strategies To Boost Anti-cancer Immunity
Funder
National Health and Medical Research Council
Funding Amount
$444,425.00
Summary
This project will determine if new immune inhibitory checkpoints can be synergistically targeted with BRAFV600E inhibition to reactivate and allow NK cells to maximise their anti-tumour immune functions and prevent cancer spread. It is a completely novel approach that will allow for the more rational design of melanoma treatments that targets NK cells following surgery and local radiotherapy and/or chemotherapy.
In various kidney diseases including the most common cause of end stage kidney disease, diabetic nephropathy, identifying the molecular mechanisms responsible for kidney failure will greatly assist in defining new therapeutic targets in order to develop new treatments and therapies. The studies described in this proposal highlight the involvement of a novel class of small RNA molecules, and provide us with a novel approach to tackle this disease.