British Skin Foundation Studentship Available in Hamill Lab

See below for details;

PhD Studentship: Dissecting the Role of LaNts and their Receptors in Epidermal Wound Healing and Squamous Cell Carcinoma.

Stipend: £13,863 pa

Institute of Ageing and Chronic Disease, Department of Eye and Vision Science

Location: Liverpool

Project starting date: 1 December 2014

Closing date for applications: Friday 27 June 2014

Eligibility: UK or EU citizens only

Supervisors: Dr Kevin J Hamill and Professor Colin Willoughby

Research Project

All forms of tissue remodelling, including wound repair and tumour cell invasion, requires coordinated modification to the extracellular matrix (ECM), the cytoskeleton and to cell-matrix interactions. Expanding our fundamental understanding of epidermal wound repair and squamous cell cancer invasion and

metastasis is a critical step to identifying new therapeutic strategies in these areas. This project will

investigate the roles of a recently identified family of small, secreted proteins, which our preliminary data strongly implicate as being important regulators of both these processes. These proteins, termed LaNts, structurally resemble a family of extracellular signalling molecules, the netrins, which have defined roles in the regulation of cell migration during nerve growth, organogenesis and tumourigenesis. By analogy, we hypothesise that the LaNts may be the skin equivalent of the netrins. This studentship is designed to characterise the role of the LaNts and netrin receptors in skin biology with particular emphasis on the regulation of keratinocyte motility, proliferation and invasion. The work is split into two connected parts. In the first, the LaNt receptors will be identified, the signalling cascades modulated by them characterised and the phentoypic consequences of those signalling events will be dissected in cell lines derived from normal and SCC sources. In the second part, the student will approach the same questions from the side of the netrin receptors. Through a combination of knockdown and rescue experiments each receptor expressed by keratinocytes will be investigated for its contribution to wound repair, tumour invasion and metastasis. The data garnered in these cell culture and 3D tissue equivalent based assays will provide the launch point for future in vivo experiments and, in the longer term, for therapeutic development.

 

The student undertaking this project will develop expertise in core molecular and cellular biology techniques and also learn valuable skills in the use of complex model systems and cutting edge microscopy techniques and therefore will become extremely competitive for future academic or industry positions.

This project will be primarily supervised by Dr Kevin J Hamill, a lecturer in the Institute of Ageing and Chronic Disease at the University of Liverpool with additional supervision from Professor Colin Willoughby.  

 

The Institute of Ageing and Chronic Disease and its constituent departments are fully committed to promoting gender equality in all activities. In recruiting researchers and academic staff we stress the supportive nature of the working environment and the flexible family support that the University provides. The Institute has recently been awarded a bronze Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

 

References

  1. Hamill KJ, Langbein L, Jones JC, McLean WH. Identification of a novel family of laminin N-terminal alternate splice isoforms: structural and functional characterization. J. Biol Chem, (2009) 284:35588-96.
  2. Hamill KJ, Kligys K, Hopkinson SB, Jones JC Laminins: Complex Molecules with complex assembly States. J Cell Sci, (2009) 122:4409-17
  3. Hamill KJ, Hopkinson SB, Hoover P, Todorovic V, Green KJ, and Jones JC. Fibronectin expression determines skin cell motile behavior. J Invest Dermatol (2012) 132, 448-457.
  4. Hopkinson SB, DeBiase PJ, Kligys K, Hamill K, Jones JC. Fluorescently tagged laminin subunits facilitate analyses of the properties, assembly and processing of laminins in live and fixed lung epithelial cells and keratinocytes. Matrix Biol, (2008) 7, 640-7

 

 

Funding Notes

This project is supported by a three-year award from the British Skin Foundation which covers annual UK fees and a stipend at the Research Council UK rate. Consideration will be given to overseas applicants who have additional funding to make up the difference in fee rates.

For further details or for an informal discussion please contact Dr Kevin Hamill khamill@liverpool.ac.uk

 

Interviews are expected to be held around 10 July. To apply for this opportunity please send your CV and covering letter by email to Dr Kevin Hamill khamill@liverpool.ac.uk with a copy to iacdpgr@liv.ac.uk

 

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BBSRC Grant Funded!

My first post and its big news! The Biotechnology and Bioscience Research Council have decided to fund my application “Characterisation of LaNt regulation of basement membrane organisation in wound repair and angiogenesis.” Exciting times!

Below is the summary from the proposal. Please feel free to comment with ideas, suggestions, feedback, collaboration ideas etc.

Characterisation of LaNt regulation of basement membrane organisation in wound repair and angiogenesis In this work I propose to study the LaNt family of proteins which were recently identified and which I believe are important for processes such as wound repair, blood vessel growth and the spread of tumours. Through these studies, a deeper understanding of these processes will be obtained and this, in turn, may lead to identification of new treatment approaches for conditions such as chronic or slow-healing ulcers and cancer.   The different tissues of the body are composed of defined combinations of specialised cell types and a mixture of proteins and sugars outside the cells, termed the extracellular matrix (ECM). Some of the cell types reside in and contribute to the production of this ECM, whereas others cover the outer (epithelial) and inner (endothelial) surfaces of regions of ECM as sheets of cells. Directly beneath these cell sheets, as well as surrounding nerves and muscles, there is an organised region of ECM termed basement membrane (BM). BMs provide the anchorage point for cells and are therefore important for stress resistance and structural integrity. In addition, BMs support the different behavioural requirements of a wide range of cell type at different times, including acting as the road upon which the skin cells migrate to close wounds.   A major component of all BMs is the laminin family of proteins. Laminins assemble into cross shaped molecules that associate with one another to form a network. Formation of this network has been shown to involve a small region at the very end of the short arms of the laminin cross, which is termed a LN domain. The importance of this interaction is exemplified by a number of genetic diseases where specific defects in LN domains impact the laminin network and BM organisation resulting in skin blistering, eye defects, kidney failure or muscular dystrophy. However, despite this knowledge, the ways in which laminin networks form, how network organisation changes during different cellular processes and what drives those changes is yet to be fully understood.   This project will focus on the LaNts which have been demonstrated to play a role in cell attachment and migration and which my preliminary data indicate is likely to be through regulating BM formation. Like the laminins, the LaNt (Laminin N-terminus) also contain a LN domain, this suggests that they can interact directly with laminins and modify the ways in which laminin networks are organised. Importantly, there are also tissue specific differences within the laminin family and these differences are likely to mean that the impact of the LaNts is cell type specific. This may also mean that LaNts play different roles during blood vessel growth or wound repair than during normal tissue function.   In order to characterise the roles of LaNts in BM formation and the impact they have on cell behaviour and tissue function, this project will pursue three aims.

  • In Aim 1, I will use proteins in solution to directly assess the ability of LaNts to interact with laminins and other BM proteins and to determine their impact on network formation.
  • In Aim 2, I will use skin and corneal epithelial cells and blood vessel endothelial cells to study the impact of changing LaNt protein levels on cell behaviour. Specifically, we will determine if the BM deposited by cells changes in response to increasing or decreasing LaNt levels and we will assess cell movement speeds, how strongly they attach and how rapidly they divide on the different substrates.
  • In Aim 3, I will use three dimensional models of skin, eye and of blood vessel growth to study LaNt roles in these more complex tissue models.

Together the data obtained from these studies will dramatically expand what is known about LaNts, about laminin network formation, about BM organisation and ultimately about wound repair, blood vessel growth and tumour progression. In the longer term, this may translate into identification of new strategies for therapy development .