Molecular Mechanisms Of Receptor Activation And Signalling
Funder
National Health and Medical Research Council
Funding Amount
$571,980.00
Summary
Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. The great majority of such stimuli are sensed by G-protein coupled receptors (GPCR), complex glycoprotein molecules on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although GPCRs are a superfamily of proteins that now compromise several ....Fundamental to our ability to respond to both immediate and long-term environmental changes and stresses is the coordinated regulation of cellular functions by hormonal and neurotransmitter stimuli. The great majority of such stimuli are sensed by G-protein coupled receptors (GPCR), complex glycoprotein molecules on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although GPCRs are a superfamily of proteins that now compromise several hundred distinct but structurally-related members, the molecular mechanisms involved in their activation and, thus, their regulation of vital cellular functions, remains unclear. Based on insights that we have gained from the development and characterisation of several alpha1-adrenergic receptor mutants, we have developed a model of receptor activation. In this application we are proposing to further test and to extend the hypotheses underlying this model. Importantly, the functions regulated by GPCR include vital responses, such as the maintenance of circulatory homeostasis by augmenting heart pump function and by constricting vascular smooth muscle to maintain blood pressure. In addition, disordered cellular regulation by GPCR has been implicated in a wide variety of diseases, including hypertension, congestive heart failure and cardiac hypertrophy. Thus, the studies detailed here to further understand the molecular mechanisms of receptor activation have broad implications for our knowledge of critical physiological control systems, and may lead to novel therapeutic approaches to treat a variety of diseases.Read moreRead less
Prion-like Behaviour In Immunity: Super-sized Signalling Platforms?
Funder
National Health and Medical Research Council
Funding Amount
$611,995.00
Summary
Prions have been mostly associated with pathologies but recent discoveries show that prion-like behaviour may be beneficial, enhancing our immune response for example. To test this, we want to systematically explore all human proteins involved in the defence against pathogens, find new prion-like trends and probe their role in the innate immune response.
Signalling Networks As Targets For Antibody Therapy In Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$526,683.00
Summary
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate antibodies that bind to receptors on the surface of can ....Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate antibodies that bind to receptors on the surface of cancer cells and block their function. If you target a receptor critical to the growth or survival of a cancer cell in this way, then swtiching-off this signal may inhibit tumor growth. In this proposal we plan to test a panel antibodies that recognize receptors important to the growth of brain cancer. Two of these antibodies have been generated and the other two will be made as part of this proposal. A key aspect of this proposal will be testing these antibodies in combination to determine how many receptors need to be targeted in order to get complete tumor regressions in animal models. Overall this work will help us identify new therapeutic strategies for the treatment of brain cancer. Finally, we will also analyze the way different receptors interact together in brain cancer cells.Read moreRead less
Signalling Pathways And Fungal Virulence – The Inositol Polyphosphate Kinase Pathway In Cryptococcus Neoformans
Funder
National Health and Medical Research Council
Funding Amount
$545,189.00
Summary
Bloodstream fungal infections kill millions of people per year world-wide and are costly to treat. A potentially fruitful strategy for developing new, urgently-needed drugs to fight these infections, is to target signalling pathways, which in fungi, are essential for establishing infection. This proposal investigates how one such pathway, the inositolpolyphosphate kinase pathway, allows fungi to establish infection and will determine which components are suitable targets for drug development.
Cognitive Enhancement In Schizophrenia Via Selective Oestrogen Receptor Modulator.
Funder
National Health and Medical Research Council
Funding Amount
$396,380.00
Summary
Cognitive dysfunction in schizophrenia is resistant to treatment and related to poor community functioning and quality of life. In spite of the widely appreciated magnitude of the problem, there is still a critical gap in our knowledge concerning treatments to reverse these cognitive deficits. The proposed research is significant because it will clarify the role of hormones and genes in relation to cognitive deficits in schizophrenia and it may help patients improve their level of functioning.
Unravelling The Behavioural And Brain Mechanisms Of Compulsive Disorders, And New Ways To Treat Them
Funder
National Health and Medical Research Council
Funding Amount
$635,076.00
Summary
Disorders of compulsion, such as obsessive-compulsive disorder and substance use disorder, are chronic, debilitating, and present a significant cost to the individual and to society. Together, these disorders affect more than 10% of the population. Moreover, 40-60% of these individuals are resistant to current treatment. The current project is aimed at improving the preclinical research underlying our understanding the behavioural and brain mechanisms of such disorders and how to treat them.
Genomic Analysis Of DNA Binding And Gene Regulation By The Chromatin Remodelling Factor UBF
Funder
National Health and Medical Research Council
Funding Amount
$624,254.00
Summary
Synthesis of ribosomes, the cellular protein synthetic machinery, is the major anabolic event of a growing cell and is frequently dysregulated during disease such as cancer. This grant will examine a protein termed UBF that we think plays an important role in orchestrating the cellular response to dysregulated ribosome biogenesis. By understanding how UBF functions we hope to uncover novel therapeutic approaches to treat diseases associated with ribosome stress .
Activation Of BMP4 Signalling To Inhibit Breast Cancer Metastasis
Funder
National Health and Medical Research Council
Funding Amount
$748,742.00
Summary
The spread of cancer cells to other organs is a common cause of breast cancer-related death in women. Current therapies for advanced breast cancer are often palliative since the secondary tumours become resistant to the chemotherapy. Here, we are using preclinical models of advanced breast cancer to develop a treatment that should be effective in patients with secondary tumours and should reduce the risk of dying of this disease.