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Centenary Institute - Medical Research

Vascular Biology Program

Our Vascular Biology program incorporates a mixture of basic and clinical science to research the blood vessels in our body. Blood vessels supply every organ in our body with blood and nutrients. As a result they are also central to most diseases, especially the chronic inflammatory diseases. We investigate the two main cells that form blood vessels – endothelial cells and smooth muscle cells.

So by understanding these cells, and their role in vascular system, we are looking diseases, such as, Alzheimer’s and diabetes. As well as many heart diseases and the basis of heart attacks and strokes.

Understanding Disease

Our vascular biology research focuses largely on diseases of the aorta and diseases involving leaky blood vessels, including age-related macular degeneration, peripheral vascular disease, stroke and solid tumour growth.

Vascular leak is a hallmark of chronic inflammatory diseases, as well as the new blood vessels formed in cancer. Thus, an understanding of how vessels become leaky crosses all aspects of cancer, inflammation and cardiovascular disease. It is through this understanding that we are able to develop drugs that may inhibit or limit blood vessel leakiness.

Through our research, we have identified a molecule that is a ‘guardian of our arteries’ and protects us from the hardening of arteries, or atherosclerosis, the basis of heart attacks and strokes. We have also identified factors that can induce vascular leak, as well as factors that can inhibit vascular leak.

Finding a Cure

Using our understanding of how the vessel controls endothelial cell integrity, we have recently identified microRNAs (small junk-like DNA) that also play a critical role in changing cell junctions. These microRNAs are altered in disease and are good targets for the development of therapeutic drugs.

We have developed a first-in-class drug that is able to inhibit vascular leak and improve the outcomes of disease, as tested in pre-clinical models of peripheral ischaemia, tumour growth and eye disease.

There is an urgent need for drugs that specifically target vascular leak, as there are none on the market against this aspect of disease.

The development of an effective drug against vascular leak will have major impact on human health for a broad spectrum of diseases, including stroke, cancer, cardiovascular disease and eye disease.

Professor Jenny Gamble, Head of Program

Phone: +61 2 9565 6100
Email: j.gamble@centenary.org.au

Additional roles:
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 endothelial cell function particularly in the area of inflammation, and how dysfunction can influence disease. Her initial publication in this area established the endothelium as a dynamic organ, central to the control of inflammatory processes.

Diseases being investigated include cancer, atherosclerosis, metabolic disease, oedema and thoracic aortic aneurysms.

The current studies in the Vascular Biology Program are under four broad areas:
1.understanding ageing of the endothelium and its impact on vascular function. Age is the greatest risk factor for the development of many diseases such as cardiovascular disease and cancer. Understanding the consequences of the ageing process to endothelial cell function will influence our ability to help us “age better”.

2. novel regulators of angiogenesis. Our genetic screens have identified genes that control endothelial cell function. One such gene impacts on tumour progression, metabolism and liver fibrosis. We are studying the mechanism of action of this gene, at the structural and functional levels

3.microRNA regulation of oedema and angiogenesis. MicroRNAs are small non-coding RNA, that control more than 30% of our protein coding genes. Thus they are known as regulators of major biological systems. Further they are often dysregulated in disease. Oedema is a critical feature in pathologies such as stroke and myocardial infarcts and angiogenic vessels in tumours are highly leaky. Limiting oedema can result in improved outcomes. We have identified a suite of microRNAs than influence vascular oedema and these are being studied as possible therapeutic candidates. Some of these microRNAs also regulate angiogenesis.

4.diseases of the Aorta. This is within the newly established Agnes Ginges, Diseases of the Aorta Laboratory, headed by Dr Renjing Liu and was established in collaboration with Prof Richmond Jeremy, Royal Prince Alfred Hospital. Initially we are focussing on thoracic aortic aneurysms which affect 1:500 to 1:1000 people and which can result in sudden death. Our aim is to identify the molecular determinants of disease progression, using animal models and extensive archival human material, which will expose opportunities to influence disease outcome.

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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.

Cell Signalling

The Cell Signalling laboratory research how blood vessel and heart form and how they maintain their function at molecular and cellular level. Our cardiovascular system delivers oxygen, nutrients and circulatory cells to every part of the human body and removes metabolic wastes. This precisely regulated development and function of heart and blood vessels are essential for the normal function of every organ system in our human body.