Angiotensin AT2 Receptor: A Novel Target For Cardiovascular Modulation
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
The hormone, angiotensin II, circulates in the blood and increases blood pressure and thickens the heart and blood vessels, all of which contributes to high blood pressure (hypertension). Angiotensin II causes these excitatory effects by acting at particular target sites called AT1 receptors. Drugs called AT1 receptor antagonists are known to block these excitatory actions of angiotensin II at AT1 receptors. Consequently, these compounds lower blood pressure in humans because they block the ongo ....The hormone, angiotensin II, circulates in the blood and increases blood pressure and thickens the heart and blood vessels, all of which contributes to high blood pressure (hypertension). Angiotensin II causes these excitatory effects by acting at particular target sites called AT1 receptors. Drugs called AT1 receptor antagonists are known to block these excitatory actions of angiotensin II at AT1 receptors. Consequently, these compounds lower blood pressure in humans because they block the ongoing stimulatory action of angiotensin II. However, it is now thought that angiotensin II may also be able to act at another target site (AT2 receptor) to cause opposite effects, i.e. decrease blood pressure and inhibit growth effects. Therefore, this project will examine if direct stimulation of AT2 sites can alter blood flows measured in different body regions in hypertensive rats as part of their mechanism to lower blood pressure. In addition, the effects of continuous stimulation of the AT2 site will be examined in hypertensive rats which will be implanted with a radiotransmitter to measure blood pressure without interference, and afterwards, structural measurements of the heart and blood vessels will be made. Additionally, this project will investigate whether stimulation of the AT2 site also contributes to the blood pressure-lowering effect of drugs already mentioned (AT1 receptor antagonists). The rationale for this is that the hormone angiotensin II is still 'free' to act at the AT2 site, even with AT1 receptors being blocked, and lower blood pressure. These studies will determine if stimulation of AT2 sites contributes to the beneficial effects (i.e. decreased blood pressure and decreased cardiovascular growth) of AT1 receptor antagonists in the treatment of high blood pressure. More importantly, these findings may also identify a new therapeutic target site (AT2 receptor) for drug development in the treatment of cardiovascular disease.Read moreRead less
Potent Small Molecule Modulators Of A Complement Protein In Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$689,428.00
Summary
We have invented powerful new compounds that act on the cell surface and regulate inflammation. We plan to (1) fine-tune our small molecules for optimal activity on different kinds of immune cells; (2) understand mechanisms by which the compounds affect cellular inflammatory responses; (3) evaluate the compounds as potential treatments in rodent models of inflammatory diseases implicated from cell studies. This study is anticipated to lead to clinical studies for a new kind of drug treatment.
Downsizing A Human Protein To Modulate Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$516,793.00
Summary
We have discovered how to downsize a human protein to very small molecules with the same activities and potencies. Small changes enable the compounds to powerfully block the actions of the protein. These small molecules are very stable in blood, whereas the protein deactivates in minutes. This project will develop the small molecules into experimental drugs and test them in human cells and proteins, and in rats to evaluate their potential for treating human inflammatory diseases.
Chronic pain is a significant global health, economic and social problem, with the annual economic burden estimated at approximately $40 billion in Australia. My research will focus on the discovery and structure-function of venom peptides (trivially called toxins) from cone snails and spiders plus other Australian venomous creatures that modulate sodium and calcium channels in peripheral pain and associated pathways and optimise these for clinical development.