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Inter- and intra-cellular signalling in the development of fibrosis in the hypertensive heart


School of Biological Sciences

About the Project

"Background

Heart failure is a leading cause of morbidity and mortality worldwide. In terms of volume, the normal heart is composed mostly of terminally-differentiated contractile cells (cardiomyocytes), responsible for the pump action of the heart. These cells require an efficient blood supply provided by the coronary arteries feeding an extensive capillary network. Consequently, endothelial cells (lining all of the vessels) form the largest number of cells in the heart. Fibroblasts are generally accepted to be the cells in the normal heart that produce the extracellular matrix necessary for the heart to withstand the stresses associated with pump action of the heart. In pathophysiological situations (e.g. hypertension or myocardial infarction), cardiomyocytes hypertrophy (i.e. increase in size in the absence of cell division) to maintain or increase cardiac output. This is associated with an increase in oxygen demand requiring an increase in the capillary network, and angiogenesis (formation of new capillaries) is required. However, as the heart adapts, there is an increase in the amount of connective tissue produced by fibroblasts or fibroblast-like cells. This compromises contraction of the heart.

Although generally considered that the fibroblast-like cells derive from the pre-existing fibroblasts in the heart, other cells may contribute to this pool of cells including those from the blood vessels. Reducing this fibrosis will clearly help to improve cardiac function and, therefore, reduce the rate of progression to heart failure. In order to do this, it is first necessary to establish the origin of the cells and the mechanisms associated with their transformation into matrix-producing cells.

Aims

This project will explore the origins of the fibrosis that develops in the heart during hypertension-induced cardiac hypertrophy as it progresses to heart failure. The aims are to identify the cellular source(s) of the fibrosis, examine the intracellular signals that promote fibrosis and identify the cues from other cells in the heart (i.e. intercellular signals) that initiate and then propagate the fibrotic response.

Experimental techniques

We will use in vivo mouse models, in addition to ex vivo (perfused hearts) and in vitro (cells in culture) systems. A range of biochemical, cell biology and molecular biology techniques will be used (e.g. quantitative PCR, western blotting, primary cell culture, immunofluorescence microscopy, protein kinase assays etc.).

Knowledge and training

Work experience in a molecular biology laboratory would be useful, but training in all techniques can be provided. Training will be provided specifically for heart research systems (primary cultures, ex vivo heart perfusions, in vivo assessment of heart function). An interest in intracellular signalling and understanding of cell biology/biochemistry is important. The position would suit an individual with a particular interest in biomedical research.

Importance

The data from this project will provide fundamental understanding of mechanisms associated with fibrosis in the heart, potentially allowing identification of therapeutic targets for treatment of heart failure and other diseases associated with fibrosis.
"



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