Development Of A Highly Potent, Fully Human Anti-GM-CSF Monoclonal Antibody
Funder
National Health and Medical Research Council
Funding Amount
$334,000.00
Summary
Many diseases, such as arthritis, have unwanted inflammatory reactions. Better drugs are needed to control inflammation. A powerful antibody to a significant pro-inflammatory cytokine will be generated; this antibody will be especially designed so that it will not be rejected by patients. Because of its properties it will cost the community less than similar therapeutics. Because inflammatory diseases are common many patients will benefit from our therapeutic.
Focus On Molecular Mechanisms By Which Cells Kill Themselves.
Funder
National Health and Medical Research Council
Funding Amount
$4,366,120.00
Summary
The main aim of this Fellowship is to enable me to further expand, enhance, and strengthen the study of cell death at La Trobe. I wish to establish a centre for bio-medical research at La Trobe that acts collaboratively with local, national and international researchers to conduct basic research and harness the results to develop new therapies. Since moving to La Trobe in January 2006 I have been able to build and expand the critical mass of cell death researchers by recruiting laboratory heads, ....The main aim of this Fellowship is to enable me to further expand, enhance, and strengthen the study of cell death at La Trobe. I wish to establish a centre for bio-medical research at La Trobe that acts collaboratively with local, national and international researchers to conduct basic research and harness the results to develop new therapies. Since moving to La Trobe in January 2006 I have been able to build and expand the critical mass of cell death researchers by recruiting laboratory heads, post-doctoral fellows and several PhD and Honours students. These have joined post-docs, who moved with me from WEHI. We continue to have very close links with the WEHI Cell Death NHMRC Program Grant I remain a Chief Investigator on that grant, renewed in 2006. Because many of the WEHI facilities are on the La Trobe campus at Bundoora, my lab has better access to new mouse strains, monoclonal antibody production, medicinal chemistry, and genetically modified mouse production than those at WEHI in Parkville. This Fellowship will allow me to accelerate the building of a research group that will make substantial collaborative contributions to the basic scientific study of the mechanisms of cell death, to identification of therapeutic targets, to testing and validation of novel pharmaceutical compounds in vitro, and to facilitate clinical trials in Australia. Australian research on the basic mechanisms of cell death is not just of international standard, it is world leading. While it is important that our research is funded to maintain this position, we do not see ourselves as competing with overseas groups, but participating in a joint scientific effort. The translation of basic findings into new treatments will require the input from pharmaceutical industry that Australia lacks. To shorten the time for clinical translation, and to benefit from these developments, we must retain our research credentials, and remain collaboratively integrated with the international effort.Read moreRead less
The Functional Roles Of ADAMs In The Regulation Of Embryo Implantation.
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
The initiation of pregnancy in humans and rodents hinges upon the ability of the embryo to attach to the wall of the uterus and invade into the uterine tissue. This process of embryo implantation is tightly regulated and depends on the secretion of enzymes and regulators of these enzymes. A newly identified family of enzymes which might be important in this process is the ADAMs family. These enzymes have the potential to facilitate both cell attachment and cell invasion and also to activate othe ....The initiation of pregnancy in humans and rodents hinges upon the ability of the embryo to attach to the wall of the uterus and invade into the uterine tissue. This process of embryo implantation is tightly regulated and depends on the secretion of enzymes and regulators of these enzymes. A newly identified family of enzymes which might be important in this process is the ADAMs family. These enzymes have the potential to facilitate both cell attachment and cell invasion and also to activate other enzymes and growth factors. Recent studies in our laboratory have shown the ADAMs to be expressed both at the most invasive time of implantation and when invasion is being down-regulated. This project will examine the role of the ADAMs in embryo implantation facilitating attachment and invasion into the uterus by acting enzymatically on the uterine tissue and by activating other enzymes. It will also determine the role of ADAMs in down-regulating invasion potentially by activating a growth factor, TNF-alpha. Knowledge of this process and particularly its regulation is important for the treatment of pregnancy associated diseases that arise from improper implantation. These include infertility, placenta accreta, choriocarcinoma, miscarriage and pre-eclampsia. Furthermore, an understanding of the regulation of implantation will contribute to the treatment of other conditions associated with cell invasion such as cancer metastasis.Read moreRead less
Modulating Interactions Between TNFalpha And IGF-1 Signaling Pathways To Reduce Necrosis Of Dystrophic Muscle
Funder
National Health and Medical Research Council
Funding Amount
$476,515.00
Summary
Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attracti ....Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attractive options for treatment of DMD patients due to their high specificity of action and relatively few side effects. We have shown that both of these drugs have a striking protective effect and reduce necrosis of dystrophic muscle in the mdx mouse. The benefits of these drugs (and the mouse equivalent cVIq) is due to blocking the action of the key pro-inflammatory cytokine Tumour Necrosis Factor-alpha (TNFa). However, the precise mechanism by which high levels of TNFa increase necrosis of dystrophic muscle is not clear. There are many possible pathways. Identifying which is the key pathway(s), is of central importance to design and target new drugs to treat such lethal muscle diseases. Such modulation of signalling is a major therapeutic goal. To determine which mechanism of TNFa action is responsible for muscle necrosis, experiments will investigate several signalling pathways using specific inhibitors: the drug Pifithrin to inhibit p53; soluble RAGE to block RAGE (Receptor for Advanced Glycation Endproducts); and specific inhibitory peptides to block JNK (c-Jun N-terminal kinase). The application of these inhibitors (drugs), in mice, as future therapies for muscle diseases is novel. These studies will provide much new information on TNFa related signalling that is highly relevant to the potential treatment of many diseases, including muscle wasting that is a major problem in the ageing population and in disuse atrophy and cachexia.Read moreRead less
The C-type Lectin, Mincle, Is A Macrophage Receptor For Candida Albicans.
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenge ....The yeast Candida albicans is an important opportunistic infection that causes both mucosal and disseminated disease in patients whose innate or adaptive immune responses are impaired Infection and proliferation results in fungal colonisation of the tissues, and a variable degree of tissue damage. The latter is determined both by the virulence properties of the organism and by the genetic makeup of the host. This large, extracellular pathogen is eradicated from the body predominantly by acavenger (phagocytic) cells, which are also important in determining the severity of the associated tissue lesions. A phagocytic cell that is central to both innate and adaptive immune responses is the macrophage, which not only takes up and kills the yeast, but also is capable of of killing and digesting it, and presenting the components to cells of the adaptive immune system. This project is based on the postulate that the outcome and severity of infection is determined, at least in part, by the early functional response of the macrophage to the overall virulence properties of the yeast. The response is initiated by interactions with cell-surface receptors, and this study will show that a novel macrophage receptor, Mincle, is an important part of the innate immune response to fungal infections. We have shown that it is associated with differences in susceptibility to yeast infections in inbred mouse strains; it can discriminate between different isolates of the yeast; and it initiates the inflammatory signalling cascade. Our project will define the specific role of this receptor in fungal infection. The results will be important in understanding the basic biology of host resistance, and will offer new opportunities for therapeutic intervention by selectively blocking or modifying different activation pathways.Read moreRead less
Mechanisms Underlying The Effects Of TNFalpha In Bone And Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$589,425.00
Summary
Recent studies have identified that bone plays an important role in blood cell production. We have discovered that elevated levels of TNF alpha (which increases with ageing and can negatively impact on health) contributes to a blood cell disorder that can progress to leukaemia. There are also reduced numbers of blood stem cells and bone in this mouse model. In these studies we will determine how TNFalpha contributes to blood and bone defects, which may lead to better treatment of such diseases.
Viral Targeting Of STAT Proteins: Roles In Disease
Funder
National Health and Medical Research Council
Funding Amount
$536,985.00
Summary
The capacity of viruses to evade the host immune response is critical to the development of disease. We recently showed that interaction of specific viral proteins with host immune proteins called STATs is vital to lethal disease caused by lyssaviruses. In this project, we aim to define in detail the functions of these interactions in viral modification of host biology and evasion of the immune response, and to use this information to develop new vaccines against highly pathogenic human viruses.
Understanding Neuroinflammation In Alzheimer's Disease
Funder
National Health and Medical Research Council
Funding Amount
$1,043,216.00
Summary
This project opens a new line of enquiry into the cellular signalling mechanisms involved in the progression of AD and establishes whether targeting the involvement of type-1 IFN signalling influences the evolution of AD. New and novel approaches are clearly required to treat AD. Importantly, we believe that neuroinflammation is common to all causes of dementia and targeting the neuroinflammatory pathways has much wider implications than targeting the primary causative pathway.
Controlling Neuroinflammation In Alzheimer's Disease
Funder
National Health and Medical Research Council
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.