PhD Scholarship in Medicine

http://www.mawa.asn.au/grants.html

Vascular Disease in Diabetic Pregnancy

Interactions of human monocytes/macrophages and decidual endothelial cells in the development of vascular disease in diabetic pregnancy, Dr Eileen Gallery, Renal Research Group, Royal North Shore Hospital, Sydney.

Diabetes is a common complication of human pregnancy and results in a number of short- and long-term problems in both the baby and mother. In pregnancies complicated by diabetes, evidence of vascular disease is visible as lesions surrounding blood vessels in the wall of the uterus.

Animals have been widely used to study diabetic pregnancy but since animal models do not adequately reflect the abnormalities occurring in human disease, there exists a need to establish systems using available human tissues. Dr Gallery has been awarded $22,120 for her study, in which she proposes to obtain from the uterine wall of pregnant women, white blood cells (macrophages) and cells which line the mothers blood vessels (endothelial cells). These two cell types will be placed in contact and their interactions closely examined. Comparisons will be made between cells obtained from normal pregnant women and from diabetic women to clarify whether abnormal interactions between these cell types could account for the development of vascular disease in diabetes. A better understanding of cellular interactions in normal pregnancy and those complicated by diabetes will benefit not only pregnant women and their babies, but also the wider diabetic community with improved strategies for treatment and prevention.
The Development of Benign Prostatic Hyperplasia

Protein Kinase C and the development of Benign Prostatic Hyperplasia, Dr J.M. Haynes, Prostate Research Group, Department of Medical Laboratory Science, RMIT University, Melbourne.

Benign prostatic hyperplasia leading to urinary difficulties is a major problem in men over the age of 60 years. Our understanding of the mechanisms that regulate human prostatic growth is sparse. Dr Haynes has been awarded $16,530 for research into prostate problems using human prostatic tissue.

The prostate is a muscular gland present in all men; it sits below the bladder, surrounding the urethra. As men get older the prostate may increase in size, resulting in difficulties urinating due to the occlusion (closing) of the urethra. Compounding the effects of increased prostate mass, the prostatic smooth muscle will contract - leading to further occlusion of the urethra. The only causal factors in the development of benign prostatic hyperplasia (BPH) are age and sex hormones (mainly androgens). Animal models have been used to investigate prostate function but have provided little toward the development of novel therapeutic strategies to combat BPH, largely because the aetiology of the disease is unknown. In this study we propose to investigate the role of intracellular enzymes in modulating human prostatic tissue function. We have previously developed the methodologies required to culture human prostatic cells in this laboratory. Using these methods we will identify (some of) the factors regulating prostatic cell growth and contractility (muscle contraction). The use of human tissue in investigating an almost exclusively human disease may enable the rapid development of new strategies to treat this condition.
Skeletal Effects of Exercise during Growth in Females

A longitudinal study of the skeletal effects of exercise during growth in females, Dr K. Bennell, Ms B.L Matthews, School of Physiotherapy, University of Melbourne; Dr K.M. Khan, School of Human Kinetics, University of British Columbia, Vancouver, Canada; Assoc. Professor J.D. Wark, Department of Medicine, Royal Melbourne Hospital.

Osteoporosis and an increased rate of bone fracture are major problems in post-menopausal women. Much of this is due to a poor diet and lack of exercise during adolescence. To address this issue Dr. Kim Bennell and her colleagues have been awarded $7,780 for a study on the effects of weight-bearing exercise on the bone density of adolescent female ballet dancers.

Exercise during growth may be important in maximising peak bone mass and thus reducing the risk of osteoporotic fracture in later life. There is little research in humans directly evaluating the effects of exercise across the adolescent growth phase. Therefore, this project will use a model already in existence as part of a three-year longitudinal study. We will continue to monitor two cohorts, one a group of healthy pubertal female dancers and the other a group of non-dancers, to assess whether exercise during childhood has a positive effect on the human skeleton. The results of this project will further promote the MAWA Trust mandate by demonstrating the use of densitometry (a method of determination of bone mass) as a safe procedure which can be used for non-animal-based research into bone density and the prevention of osteoporosis.
SCHOLARSHIPS
Transfection of an Immortalized Human Cell Line to Monitor Drug Actions

The inaugural MAWA Trust Doctoral Research Scholarship was awarded to Ms Hala Raghib of RMIT University in Melbourne, for a project entitled Death by QT: A New Safety Challenge. In her application, Ms Raghib described her project as follows:

"Recently some drugs that have been in widespread use have been withdrawn from sale because they have been associated with deaths related to cardiac disturbances, the most notable example being the antihistamine terfenadine. The safety of currently used drugs and proposed new drugs with respect to cardiac disturbances is unknown as appropriate testing, QT interval testing, is not widespread. The genesis of the QT interval relies on the activity of cardiac ion channels responsible for action potential initiation. These vary between species making the classical rodent models of testing unreliable, and currently animal experiments (for example using dogs) are recommended. "

"An alternative approach, is to transfect an immortalized human cell line with the relevant human ion channels, and use this to monitor drug actions for potential cardiac disturbances. Drugs known to affect QT in humans will then be addressed in the cell system. This will then test the predictability of the methodology with relevance to human safety testing. The study represents significant potential to replace animals in drug development."

Ms Raghib has now completed her doctoral project without resorting to the use of any animal products. Professor Harry Majewski, Ms Raghib’s supervisor and Head of the School of Medical Sciences at RMIT University, stated that the result is good in that Ms Raghib now has a human cell line which has been genetically engineered with the human HERG gene without any animal methodology, even in reagents. The MAWA Trust is pleased that this cell line is considered a useful tool and looks very promising for future research. The second project is to investigate whether the cell line can be used to screen drugs.