The program has 3 main areas under investigation:
- Endothelial cell ageing: Endothelial cells form the lining of blood vessels and they maintain the anti-inflammatory, anti-thrombotic and selectively permeable nature of blood vessels. Cardiovascular diseases, which are linked to age, all show endothelial cell dysfunction. We are investigating the molecular, biological and metabolic changes that are induced in ageing endothelial cells and how these changes could predispose us to diseases of the age.
- Alzheimer’s disease (AD): AD is an age-related neurodegenerative disease that progressively affects brain function. AD is the most common form of dementia, which is the 2nd leading cause of death in Australia. In 2019 there were approximately 500,000 Australians with dementia, of which about 70% suffer from AD. One of the new concepts in AD is that changes in the brain vasculature are an early major contributing factor to the pathogenesis. The significant change seen early in AD is in the breakdown in the blood-brain barrier, where the vessels become leaky and this occurs before the formation of the classic features of Alzheimer’s pathology, the plaques and the tau tangles. Our research is directed to understanding the molecular changes that occur in the blood vessels that result in vascular leak and the progression of Alzheimer’s pathologies.
- Calcific aortic valve disease (CAVD): CAVD is an age-related cardiovascular disease, and the most common valvular heart disease in developed countries, affecting 2-4% of those over 65 years. CAVD begins as mild sclerosis of the valve and progresses to stenosis and calcification, with increased stiffness and fusion of the leaflets. Interventions, such as aortic valve replacement or less invasive transcatheter aortic valve replacement technologies are costly, are often delayed until the late stages of the disease when left ventricular dysfunction has occurred. At present there are no drug therapies available, and few in development, largely due to the limited understanding of the underlying molecular and cellular mechanisms driving calcification. Our focus is elucidating the effect of age on the function of the cells of the valve leaflets and the process of calcification.
Finding a Cure
Understanding the fundamental biological and molecular changes that take place in cells of the blood vessel with age will expose novel targets for the development of therapeutics and for biomarkers that may help in defining disease at an early stage.
Vascular leak is an underlying feature of chronic diseases. A decrease in the integrity of the endothelial cell barrier is a major alteration that can lead to vascular leak, and such changes occur upon ageing. Hence, we are particularly interested in defining new targets for the development of drugs that will mend the damaged blood vessels, inhibit leak and which limit the progression of chronic inflammatory diseases.
Professor Jenny Gamble, Head of Program
Phone: +61 2 9565 6100
Wenkart Chair of Endothelium
Medicine, Central Clinical School
Professor Jennifer Gamble is an internationally recognised research leader in the field of endothelial cell function and holds the Inaugural Wenkart Chair of the Endothelium.
Her interests lie in understanding the function of blood vessels, particularly the endothelial cells that form the barrier between the blood and the tissues. Her initial work on the action of TNF on the endothelium to support neutrophil adhesion redefined and forms the basis for our understanding of the central role of the endothelium in inflammation.
She has been instrumental in defining the concept of positive and negative regulators of the endothelium, their role in inflammation and barrier function and the signaling pathways involved. She has identified and characterised the role of new genes which regulate endothelial cell function, with her recent work focusing on understanding endothelial cell ageing or cellular senescence. She has recently discovered the function of the gene, called SENEX or ARHGAP18, which provides a unique gatekeeper function in limiting the stress induced premature senescence and inflammation pathways in endothelial cells.
Her laboratory is expanding into studies on pericytes, smooth muscle cells and perivascular macrophages, all cells which interact with endothelial cells and which together control blood vessel function. The laboratory utilises state of the art single cell analysis, high resolution imaging, metabolic studies and animal models in their investigations.
Diseases being investigated are Alzheimer’s disease and heart disease.
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Lipid Cell Biology
The Lipid Cell Biology Laboratory is currently investigating the following projects:
1. Liver disease
The liver is the primary metabolic organ in our body. Abnormal fat deposition in the liver causes a series of conditions, including insulin resistance, fatty liver, liver fibrosis and liver cancer. Medical research on these liver diseases plays a crucial role in improving the quality of life for people with chronic illness and extending survival time for those with the fatal disease. At the forefront of medical research, Lipid Cell Biology Laboratory is focused on the study of sphingolipids, a class of essential fat products, in the liver. Dr Qi and his colleagues aim to identify key components of sphingolipids, as novel druggable targets and early diagnostic biomarkers of liver diseases.
2. Cardiovascular disease
Atherosclerosis is a chronic condition in which arteries harden and narrow due to a build-up of fatty plaque on the arterial wall. Although the use of blood cholesterol-lowering medications can be successful in halting or reducing this plaque build-up, atherosclerosis remains the leading cause of cardiovascular disease-related death worldwide. This problem needs a new solution. In addition to levels of risk factors in the blood, Dr Qi believes that how blood vessel senses the deleterious environment may also determine the outcome of atherosclerosis. Lipid Cell Biology Laboratory is now studying how fat products within blood vessel cells affect vascular fitness and disease progression. This project will open a window for the development of a new class of drugs, targeting blood vessels to treat atherosclerosis.