Understanding Allosteric Modulation And Biased Signalling At Family B GPCRs
Funder
National Health and Medical Research Council
Funding Amount
$428,065.00
Summary
Family B GPCRs are therapeutic targets for drugs treating osteoporosis, hypercalcaemia, Paget’s disease, type II diabetes and are being actively pursued for other diseases that represent major global health burdens. Despite huge financial input, there are no orally available drugs that act on these receptors. This speaks to a lack of mechanistic understanding of how they work. My research focuses on addressing this question and how to exploit these receptors to design and identify better drugs.
The Structure And Composition Of The T-cell Receptor-CD3 Complex
Funder
National Health and Medical Research Council
Funding Amount
$434,644.00
Summary
Our research will provide a fundamental advance in our understanding of how foreign viruses and pathogens trigger the immune system. Gaining a greater understanding of these central events will facilitate the design of novel therapies to treat immune associated disorders such as transplant rejection, autoimmune disease and some cancers.
Characterising The Novel Signalling Mechanism For A New Interferon
Funder
National Health and Medical Research Council
Funding Amount
$525,485.00
Summary
We have discovered a new regulatory protein called interferon epsilon, made in the female reproductive tract and is crucial for protection against bacterial( Chlamydia) and viral (Herpes Simplex Virus) infections. However, we are yet to understand how it interacts with target cells. This grant will study how IFN? binds to cells and the nature of the signals it transmits. This will help us understand its role in disease and its clinical potential
The Structural Basis For Biased Agonism At The Glucagon-like Peptide-1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$872,536.00
Summary
The glucagon-like peptide-1 receptor plays an essential role in nutrient-regulated insulin release, and is a major target for therapeutic treatment of type 2 diabetes. The binding of different drugs to this receptor can promote distinct signalling profiles inside the cell that can lead to different physiological outcomes. Understanding the mechanistic basis for this will provide a framework to enable rational design of novel, better and safer therapeutics for the treatment of diabetes.
Understanding The Structural Basis For Family B G Protein-coupled Receptor Function
Funder
National Health and Medical Research Council
Funding Amount
$745,082.00
Summary
G protein-coupled receptors (GPCRs) are the largest family of cell surface proteins that enable communication from external signals to the inside of cells of the body. Family B GPCRs are a therapeutically important subclass of these receptors and they play crucial roles in bone and energy homeostasis, cardiovascular control and immune response. This grant will uncover fundamental knowledge on how these receptors work, and will enhance future development of therapeutics.
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
In 2011 there were over 360 million people with type 1 and type 2 diabetes worldwide, who will require insulin treatment. There is an urgent need for insulin analogues that provide effective control of blood glucose to avoid unwanted hypoglycemic or hyperglycemic events. We have developed two novel insulin analogues with unique properties and aim to understand their mechanism of action. This knowledge will present new opportunities for improved insulin mimetics for diabetes treatment.