Biogerontology Laboratory
Professor David Le Couteur
The Biogerontology Laboratory, located within the ANZAC Research Institute, is the biological research arm of the Centre for Education and Research on Ageing (CERA), a joint Centre of Concord Hospital and the University of Sydney’s Department of Medicine. The role of the Biogerontology Laboratory is to investigate the biological causes of ageing and age-related diseases. There are several diverse projects available within the laboratory utilising a broad range of techniques that includes confocal microscopy, transmission and scanning electron microscopy, tissue culture, small animal surgery, HPLC and immunohistochemistry. Currently, the major emphasis is on age-related changes in the liver and the implications these changes may have for drug metabolism and the development of vascular disease in the elderly.
Project 1: The Ageing Liver
This project investigates how ageing affects the ultrastructure of the liver’s unique blood vessels, known as sinusoids, and the possible implications of these changes. The endothelium of the liver is normally very thin and perforated with pores called fenestrations that are grouped into clusters called sieve plates. As we age the number of fenestrations become fewer and the endothelium becomes thicker. These changes are thought to impact on the liver’s ability to exchange substances from the blood reducing its capacity for the detoxification and metabolism of drugs. Mechanisms that may account for these age-related changes are under investigation.
Contact: Dr Victoria Cogger,
Tel +216 9767 6929;
email:
Project 2: The Ageing Liver and Hyperlipidaemia
This project investigates the relationship between age-related defenestration of the liver sieve and the development of atherosclerosis. Following a meal a transient postprandial hyperlipidemia results as the body attempts to deal with the fat load. Ingested fat is released by the gut to the circulation in the form of large chylomicrons (lipoproteins), which are converted to smaller chylomicrons remnants in the circulation. Fenestrae within the liver control the uptake of chylomicrons remnants by the liver for further processing while excluding the larger chylomicrons. The persistence of chylomicrons or their remnants in the circulation predisposes to vascular disease.
Contact: Prof. David Le Couteur,
Tel: +612 9767 7212;
email:
Project 3: Pharmacological Modulation of the Liver Sieve
This project uses isolated liver sinusoidal endothelial cells in culture to study the role of various agents, including drugs and oxidative stress, on the liver sieve and its fenestrations. Currently, we are looking at the relationship between oxidative stress and endothelial cell morphology and liver sieve dynamics. The mobilisation of F-actin filaments, proteins that control endothelial sieve morphology, is being visualised by confocal microscopy under conditions of oxidative stress to provide insight into this process.
The reorganisation of F-actin filaments is an energy dependent process requiring the energy rich molecule ATP. We have found that decreases in cellular ATP levels result in loss of fenestrae, including loss of whole sieve plates. As mitochondria are the subcellular structures responsible for ATP production we are examining the relationship between mitochondrial dysfunction (either chemically induced or age-related) and sinusoidal defenestration. This is an exciting project that may link the mitochondrial theory of ageing with our observations of age-related sinusoidal defenestration.
The role of environmental influences on the sinusoids of the liver is an area of further investigation. In particular, we are examining the role of dietary oxidised fats (cooking oils) as modulators of liver sinusoid morphology and function.
Contact: Dr Michael Muller,
Tel: +612 9767 9160;
email: mmuller@anzac.edu.au
LIVER RESEARCH (non ageing related research)
The laboratory also conducts research into childhood genetic diseases of the liver. The hereditary disease impairs normal liver metabolism. The consequence is a build up of bile components in the liver, which produces a condition called cholestasis. Without a full liver transplant, this disease is fatal within the first decade of life. The genetic causes of the disease provide a valuable insight into basic cellular mechanisms of the liver. With a basic understanding of the mechanism, drug therapies may be possible.
Project 4: To investigate the function of FIC1 mutations on ABC transporters.
The gene that causes hereditary childhood cholestasis is known as FIC1. This protein is a P-type ATPase, a large membrane protein that transports phospholipids across a membrane. How mutations in this protein cause cholestasis is unknown and is very intriguing. The project involves development of functional assays to assess the impact of mutations in FIC1 on ABC transporters. ABC transporters “pump” bile components into the bile ducts. These transporters are ultimately affected in the disease state. The latest molecular biology techniques will be used including small interference RNA technology. Other techniques include confocal microscopy, cell culture, flow cytometry and real time RTPCR.
Contact:
Dr Matthew Harris
Tel: +612 97679106 / 97679100
Email:
Relevant reading:
- Bull LN, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat. Genet. 1998; 18: 219-224.
- Harris MJ and Arias IM. FIC1, a P-type ATPase linked to cholestatic liver disease, has homologues (ATP8B2 and ATP8B3) expressed throughout the body. Biochimica et Biophysica Acta 1633 (2003) 127– 131