A New Paradigm For Class I Cytokine Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$954,946.00
Summary
Class I cytokine receptors include around 30 receptors with diverse functions such as controlling metabolism and inflammation. Cytokine receptors are molecular switches on cells that receive signals from other cells and transmit this signal into the cell’s nucleus to control the regulation of genes. This project will determine the molecular mechanisms involved in class I cytokine receptors and use this knowledge to develop novel ways to modulate these receptors for clinical applications.
Integrated Drug Design For A New Generation Of Adrenergic Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$406,242.00
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 complex glycoprotein receptors on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although there are several hundred distinct, but structurally related receptors of this kind, including the a ....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 complex glycoprotein receptors on the surface of most cells that selectively bind and are activated by various hormones and neurotransmitters. Although there are several hundred distinct, but structurally related receptors of this kind, including the adrenergic receptors (ARs), the molecular mechanisms involved in their activation and, thus, their regulation of vital cellular functions, remain unclear. Based on insights that we have gained from the development and characterisation of several mutated ARs, we have developed a model of receptor activation. In this application we propose to further test and extend the hypotheses underlying this model. Importantly, the functions regulated by ARs include vital responses, such as the maintenance of blood pressure by augmenting heart pump function and by constricting vascular smooth muscle. In addition, disordered cellular regulation by ARs has been implicated in a wide variety of diseases, including high blood pressure, congestive heart failure and enlargement of the heart. 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, including also tumours of the adrenal gland that cause excess adrenaline secretion. The cost and length of time associated with the development of a new drug in the pharmaceutical industry are enormous, and thus many promising medicinal agents never make it to the market. We propose to contribute to the drug discovery effort by developing novel combined methods for computer-aided drug design, to allow more efficient drug development.Read moreRead less
The Biology Of Ross River Virus And Its Cellular Receptor
Funder
National Health and Medical Research Council
Funding Amount
$252,750.00
Summary
Ross River virus (RRV) causes a principally rheumatic disease in up to 8000 Australian annually. The disease is severe at onset comparable to that suffered by patients with osteoarthritis awaiting hip replacement. However, the disease usually resolves within 6 months. This grant intends to continue our studies on how and why RRV causes disease and develop an understanding of why only 1 person in 20 infected with RRV actually develops disease. We believe RRV arthritis is cause by RRV persisting i ....Ross River virus (RRV) causes a principally rheumatic disease in up to 8000 Australian annually. The disease is severe at onset comparable to that suffered by patients with osteoarthritis awaiting hip replacement. However, the disease usually resolves within 6 months. This grant intends to continue our studies on how and why RRV causes disease and develop an understanding of why only 1 person in 20 infected with RRV actually develops disease. We believe RRV arthritis is cause by RRV persisting in specific white blood cells residing within joint tissues. The grant intends to exploit the recent observation that to infect cells RRV uses a receptor, which human cells normally use to bind to collagen. Armed with this new information we intend to unravel how RRV can persist despite the patient making good antibody responses against the virus, and determine whether high levels of this receptor predispose to disease. The ultimate goal for these studies is the identification of potential new treatments for this and perhaps other arthritic diseases caused by viruses. We have also recently identified a new virus in seals that is related to RRV, but fortunately appears not to pose a health threat to humans. However, we intend to test whether this new virus uses the same receptor as RRV and begin to explore using computer technology some of mutations these viruses would need before they could successfully infect humans.Read moreRead less
Protective Roles For Protease-activated Receptor 2 (PAR2) In Parasitic And Autoimmune Diseases
Funder
National Health and Medical Research Council
Funding Amount
$483,421.00
Summary
Parasite infection has unique and specific effects on the human immune system which can prevent allergy and diseases such as diabetes and multiple sclerosis (MS). We have discovered a drug which can cause the immune system to behave in a similar way to that observed during a parasite infection. This project will explore how the drug mimics a parasite and examine the potential of this treatment to prevent MS using a mouse model of this disease.
Characterisation Of The Adiponectin Receptors - AdipoR1 And AdipoR2
Funder
National Health and Medical Research Council
Funding Amount
$445,158.00
Summary
The increasing incidence of cardiometabolic disease highlights an unmet need for novel therapeutic approaches. Greater understanding of the detail governing cardiometabolic function is required to provide a foundation to construct effective strategies. We will characterise 2 novel receptors that are important in the regulation and maintenance of cardiometabolic systems, seeking to identify strategies to enhance receptor, improve cardiometabolic function and reduce disease burden.
Molecular Pharmacology Of Chemokine Receptor Signalling In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$371,770.00
Summary
Molecular pharmacology is the study of how hormones, neurotransmitters and pharmaceuticals interact with our cells through receptors, which transfer a signal across the cell membrane to change the function of that cell. Chemokine receptors are recognised to play a role in the development of many cancers. Understanding how these receptors work has enormous implications for improving our ability to develop better anti-cancer treatments with fewer side effects.
Allosteric Targeting Of The Dopamine D2 Receptor: A Novel Approach For The Treatment Of Parkinson’s Disease And Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$469,644.00
Summary
The dopamine D2 receptor is a brain protein that is the target for drugs that are used in the treatment of schizophrenia and Parkinson's disease (PD). In both cases the current drugs have significant side effects because they simply act to switch the receptor off or on respectively. We will focus on a new class of drugs that, because they act to tune up or tune down the activity of the D2 receptor, may be a safer more effective approach to treat these disorders.
The Novel CXCR4/CCR7 Heterodimeric Chemokine Receptor Is A Key Determinant Of Breast Cancer Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$461,252.00
Summary
Novel cellular receptor has been identified that works as a switch to turn on cellular functions that are responsible for the metastatic dissemination of cancer cell to distant organs. The make-up and regulatory mechanisms of this novel receptor will be studied together with its potential utility as the marker of metastatic breast cancer.
This research will push the boundaries of current knowledge in receptor pharmacology and translate this knowledge into clinical outcomes. Receptors are proteins on the surface of our cells that bind hormones, neurotransmitters and pharmaceuticals. By better understanding the complexities of how these receptors work at the molecular level, the objective is to develop improved treatments and better clinical management for a range of medical conditions.