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
Alteration Of Glucose Metabolism By GPCR Activation
Funder
National Health and Medical Research Council
Funding Amount
$444,796.00
Summary
In type 2 diabetes the effect of insulin to stimulate glucose transport in fat cells and skeletal muscle is impaired so there is great interest in identifying insulin-independent mechanisms that increase glucose transport. Several G protein-coupled receptors (GPCRs) regulate glucose transport independently of insulin but the mechanisms involved in these effects are largely unknown. This project investigates how GPCRs regulate glucose homeostasis and will evaluate them as potential treatments.