Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.
Understanding The Function And Regulation Of G Protein-coupled Receptor Signalosomes And Their Role As High Resolution Signalling Platforms
Funder
National Health and Medical Research Council
Funding Amount
$566,588.00
Summary
G protein-coupled receptors are specialised proteins located on the surface of cells. They are the targets of 50% of currently available pharmaceuticals, but these drugs are derived from limited knowledge of only a fraction of proteins. This proposal will examine exciting and novel properties of receptors that only occur following the assembly of the proteins into specialised networks within cells. The new information will expand our current knowledge, and facilitate future targeted drug design.
Modulating Sphingolipid Signalling To Enhance Wound Healing
Funder
National Health and Medical Research Council
Funding Amount
$698,447.00
Summary
Impaired wound healing is a major problem for diabetics, who often suffer with chronic unresolved wounds with serious effects on their quality of life and mortality. We have recently discovered a new pathway involving sphingolipids that shows great promise to improve wound healing in diabetics. In this project we will examine the targeting of this pathway, using existing and newly developed agents, to improve wound healing in advanced pre-clinical models of diabetes.
Debilitating anxiety disorders, such as post-traumatic stress disorder or panic disorder, affect 14% of adult Australians and current therapy is often ineffective. The amygdala is a brain region that is key to learning fear responses but also in reducing our fear responses. This project will determine whether the brain’s own endogenous opioids can modify the activity of the amygdala in order to provide new leads for novel pharmacotherapies with enhanced efficacy.
Mechanisms Of Ligand-Selective Signalling By Chemokine Receptors
Funder
National Health and Medical Research Council
Funding Amount
$749,428.00
Summary
Receptors are molecules located on the surfaces of cells. They control the response of one cell to chemical signals emitted by different cells. In this project we aim to characterise and understand the molecular details of how a receptor can respond differently to distinct chemical signals. The results of this study will help to guide future development of medicines to control white blood cell migration into tissues during inflammatory diseases such as heart disease, diabetes and arthritis.
STABILISING G PROTEIN-COUPLED RECEPTORS FOR DRUG DISCOVERY
Funder
National Health and Medical Research Council
Funding Amount
$628,140.00
Summary
Prescription drugs targeting human proteins called GPCRs are sold as effective treatments for many diseases. However, there are over 800 different types of GPCRs in the human body and only a small fraction is targeted by drugs, mainly because GPCRs are unstable and thus difficult to work with in the laboratory. We are applying newly developed technologies to engineer stabilised ?1-adrenoceptors, a class of GPCRs, for drug discovery against cardiovascular diseases, epilepsy and neurodegeneration
Small Molecule Activators Of Glucagon-like Peptide Receptor
Funder
National Health and Medical Research Council
Funding Amount
$658,152.00
Summary
This project seeks new knowledge about (i) a protein on pancreatic cells that can be stimulated to treat problems associated with type 2 diabetes, and (ii) how to create small molecules that can act on this protein and afford a better treatment for diabetes. Advantages of such a new treatment will be low cost, easy administration as an oral tablet rather than injection, need for minimal supervision and monitoring by medical professionals, and therefore more accessibility to global populations.
Elucidating The Mechanisms Of Alpha-conotoxin-induced Calcium Channel Inhibition Via G Protein-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$419,082.00
Summary
N-type voltage-gated calcium channels (VGCCs) are membrane proteins involved in neurotransmission and play a major role in pain. VGCCs are a well-established target for the development of analgesics. Our recent research identified that VGCCs can be inhibited by ?-conotoxins from the venom of marine snails by targeting ?-aminobutyric acid receptors in sensory neurons. We will characterize this novel form of modulation of VGCCs by ?-conotoxins and define the pathways that lead to VGCC inhibition.
The hormone angiotensin II (AngII) contributes broadly to the cardiovascular, endocrine, neural and metabolic systems. It binds to the angiotensin II type 1 (AT1) receptor and inappropriate activity leads to hypertension. Using a range of molecular and biophysical approaches and the angiotensin receptor as a model GPCR, we will study the role of the cell membrane in AT1 activation which may lead to new approaches for drug design.
This project will investigate the properties of an important family of proteins that play a major role in diseases such as chronic pain and cardiovascular illnesses. It will apply multidisciplinary, cutting-edge, approaches to understand how different types of drugs act on these proteins, and use this information to develop novel drug leads that can modulate these proteins in a more selective and efficacious manner, with a particular emphasis on targeting chronic pain conditions.