Postgraduate Studies Projects

Lab Head:                Professor Jaye Chin-Dusting

Phone:                      8532 1505

Email:                        jaye.chin-dusting@bakeridi.edu.au

Lab Overview

The Vascular Pharmacology Laboratory is renowned for our work in human experimental biology and medicine. Our work centres around the endothelium and its role in inflammation and reactivity particularly in cardiovascular disease states. Studies are defined by the questions asked and limited only by the imagination of the scholar. Our projects normally extend from the bench to animal models to patients and back to the bench again. Hons and PhD scholars can expect to receive a well-rounded training in a supportive environment led not only by Professor Chin-Dusting but by the post-doctoral fellows in the laboratory: Drs Karen Andrews, Michael Skilton, Shirley Moore, Natalie Lumsden, Yi Fu and Olivier Huet.

Project 1 - A role for nitroxyl (HNO) in the treaTmenT of nitrate tolerance in human blood vessels?

Supervisors:  Dr Karen Andrews, Dr Barbara Kemp-Harper & Prof Jaye Chin-Dusting

Arteries play an important role in maintaining blood pressure as well as supplying the body with the essential nutrients and oxygen for everyday function. All blood vessels have a lining (endothelium) and an outer layer made up of vascular smooth muscle cells. The endothelium releases and produces compounds that act on the smooth muscle layer to control blood pressure and flow by contracting or relaxing (vascular tone). Nitric oxide (NO) is an important and potent compound produced by the endothelium which acts on the smooth muscle layer allowing blood vessels to dilate.

Several conditions and diseases such as atherosclerosis, hypertension, angina and coronary artery disease exhibit reduced NO production which contributes to abnormal endothelial (vascular) function and reduced blood flow. Treatment of impaired endothelial function includes administration of a drug called GTN (glyceryl trinitrite). GTN is an organic nitrate, which releases NO and increases its availability in the blood vessel and induces relaxation. However, a limitation with this drug is the development of nitrate tolerance (the effects of the drug are diminished) that occurs after long-term use. A nitrate-free period is currently the only known protection and the underlying mechanisms of tolerance appear to be both multifactorial and not fully understood.

Recent studies have suggested that nitroxyl (HNO), the reduced congener of NO^·, may be of physiological importance since studies in animals have shown it can be produced by the animal (endogenously) and the HNO donor, Angeli's salt (AS) dilates both conduit and resistance arteries. Due to the distinct pharmacology between NO^· and HNO, a role in the treatment of cardiovascular diseases has been suggested. Furthermore, AS has been shown to be resistant to the development of tolerance. However, the effectiveness of HNO donors in human vessels is yet to be established.

This project aims to assess the mechanisms of HNO mediated relaxation and its susceptibility to tolerance and will determine if HNO has the potential to be used therapeutically.  Human saphenous veins and coronary and radial arteries will be obtained from patients undergoing coronary artery graft surgery and mounted in standard organ baths to assess blood vessel function. Additional techniques included western blot analysis and oxidative stress assays. This honours project is suitable for a well motivated student with a background in pharmacology and/or physiology and an interest in clinical research.

Project 2 - Investigating the Cardiovascular Properties of Australian Plant Extracts

Supervisors: Dr Natalie Lumsden & Prof Jaye Chin-Dusting

Australian flora is unique and one of the most diverse with over 280,000 described species. The medicinal application of Australian plants has long been valued by its indigenous communities who through trial and error over thousands of years have discovered treatments for nausea, headache, diarrhoea, infections and wounds. Unfortunately, today much of this knowledge has been lost with European settlement and subsequent documented pharmacological analysis has been limited, primarily focusing on anti-microbial and anti-tumour activities. The untapped potential of Australian flora as a source of new medicines can be demonstrated by the discovery of castanospermum, a polyhydroxy alkaloid identified in the Moreton Bay chestnut (Castanospermum australe) located in northern Australia. This compound has demonstrated HIV inhibiting properties and blocks leukocyte passage though the subendothelial basement membrane. Discovery of new drug leads from Australian flora therefore may be vast and have application for treating common diseases of westernised countries such as atherosclerosis. This study aims to evaluate the cardiovascular activities of Australian plant extracts.

Honours Project details

The student will be able to gain experience in a range of techniques often utilised in cardiovascular laboratories including: tension myography and organ bath pharmacology to assess vascular activities; platelet aggregometry and blood clotting assays to identify haematological activities; cell based assays to identify activity upon common signalling pathways of the cardiovascular system e.g. cGMP and cAMP. This project will also provide the opportunity for the student to examine vascular anti-inflammatory actions of the plant extracts using a novel cell-cell based assay system.

Project 3 - Interaction between endothelium and leukocytes during septic shock.Role of P-selectin

Supervisors: Dr Olivier Huet & Prof Jaye Chin-Dusting

Septic shock is associated with endothelial dysfunction which can contribute to multiple organ failure occurrences. Interaction between endothelial cells and other blood cells takes part in microcirculation impairment during septic shock. Adhesion molecules, particularly P-selectin, are key elements of leucocytes recruitment during septic shock. Recently, P-selectin has been studied in cardiology and in cancer research. In these fields, it appears that P-selectin could be an exciting therapeutic target in the next few years. However, the exact part of P-selectin in the pathophysiology of the septic shock and the multiple organ failure syndrome is not clearly established at this time. Recent data from animal models of shock indicate that P-selectin could play a major role in leukocyte recruitment during septic shock compared to other adhesion molecules. In the current project we will examine this hypothesis using plasma from septic shock patients.   Methodology will include vessel perfusion experiments and cell-cell interaction studies using microscopic imaging.  We are seeking Hons students for this project, and PhD students who may be interested in the topic but in an extended program. Summer Vacation students keen to do an Hons year in 2010 are invited to make enquiries.