Molecular dissection of cell-extracellular matrix interactions in hepatic homeostasis and the development of fibrosis

Description

This opportunity will close as soon as a suitable candidate has been found.

The overall long-term goal is to increase our currently limited understanding of mechanisms by which extracellular matrix (ECM) contributes to liver homeostasis and the development and progression of liver fibrosis.

ECM induces a variety of signals that regulate the behaviour of cells, such as differentiation, adhesion and migration, and also fundamental physiological processes such as embryonic development and tissue regeneration and remodelling. As a consequence, tissues or organs keep their normal architecture and homeostasis. Aberrations in signal transduction from the ECM cause chronic degenerative and fibrotic disorders, but detailed molecular mechanisms still remain largely unknown despite decades of intensive study. There was a long-standing concept that cells cannot form type I collagen fibril network without ECM glycoprotein fibronectin in culture. We have established an adult mouse model lacking fibronectin in livers. We have discovered that the collagen-network is nucleated not only by fibronectin but also type V collagen induced by elevated local TGF-β-bioavailability. These findings raise hypotheses that both type V collagen and fibronectin play a significant role in adult liver remodelling, and that the extent of contribution is dependent on the temporal and spatial expression pattern of each molecule.

Liver cirrhosis is the end-stage of several clinical grade of liver fibrosis and is responsible for significant morbidity and mortality. In the UK, approximately 4,000 patients die annually as a consequence of liver cirrhosis, two-thirds of whom are aged under 65. One curative option for end-stage cirrhosis is liver transplantation but donor organ availability and costs cannot meet demand. Currently no effective treatments exist to predict and regulate liver fibrosis/cirrhosis.

In this proposed project, we will initially define the functional requirement of ECMs such as fibronectin and type V collagen to maintain homeostasis in mouse and human hepatic stellate cell lines in vitro. We will also identify modulatory roles in the hepatic ECM reorganization and remodelling in response to hepatic injuries. We will utilize variety of experimental approaches such as cell and molecular biology, biochemistry, bioengineering, and genetically-modified mice as in vivo model system.

This is an exciting body of translational research and there is also scope for a dynamic and committed student to direct their research in different directions depending on their own interests and goals. The Department of Pharmacology and Therapeutics is an excellent multidisciplinary research environment with direct links to unique technological platforms and technical expertise, ideal for the student to learn valuable laboratory techniques and skills for their future career.

We are looking for a highly motivated student who is willing to pursue cutting edge research within a vibrant and collegiate team. A basic background in hepatology and histopathology would be beneficial. The Institute of Systems, Molecular and Integrative Biology (https://www.liverpool.ac.uk/systems-molecular-and-integrative-biology/) is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides.

Essential eligibility requirements:
• BSc (minimum upper-second honours degree) in a related discipline.
• Excellent communication skills to patient and academic audience.
• Experience of quantitative physiological data collection.

For an informal discussion about this opportunity please email Dr Takao Sakai (Email: sakait@liverpool.ac.uk)

Applicants should send a CV (including two references), covering letter (2-page max), and the names of at least two references to Dr Takao Sakai directly on sakait@liverpool.ac.uk

Availability

Open to students worldwide

Funding information

Self-funded project

This is a self-funded project, and there is no funding attached to this PhD opportunity. Individuals with a scholarship or who are willing to self- fund are invited to apply for the project. Fee information can be found on the University website. In addition, research costs will be required.

Supervisors