Below is information on just some of the research
projects that we currently fund:-
Cervical Cancer
The Humane Research Trust Laboratory
A New model To Study Infammatory Signals For Barrett's Oesphagus
Cystic Fibrosis
Neurotoxicity Testing
Towards a Non-Animal Model for Testing New Drugs Against Parasites
Tetraspanins
Novel Effector of Cell Death Studied in an Eye Cancer Experimental Model
Cervical Cancer
University of Manchester, Dr's Ian and Lynne Hampson and Professor Henry
Kitchener
Cervical cancer is the most common type of cancer
in women worldwide and it has now been shown that a specific type of
virus called the human papilloma virus (HPV), is involved in causing
90% of cervical carcinomas.
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Dr Ian Hampson and Wendy Turner Webster
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What is needed is a simple, cheap, non-destructive
therapy that would permit self-administered, widespread treatment.
This would be of significant benefit in both the developed and developing
world, where there is limited patient access to clinics and lack of
medical resources.
The research aims to isolate molecularly engineered
human antibody fragments that can act inside cells to neutralise the
cancer inducing properties of HPV. The Trust has extended its original
commitment to the work in several ways.
After a large bequest The Trust is pleased to announce funding for five year's for a Post Doctoral Scientist who will aim to identify the molecular targets of human tumour viruses.
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Extension on funding for Dr Lynne Hampson
The Trust has agreed to a joint funding initiative with the University
which will enable Dr Lynne Hampson to continue working on the project
for a further four years.
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Postgraduate Studentship - Rufsan Bibi
This research has the same overall aim as the main project, but
explores alternative, complementary paths. Ms Bibi is preparing
her thesis
on this work.
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Postgraduate Studentship - Anthony Oliver
Mr Oliver will be continuing the work begun by Ms Bibi and will
also study the effects of the HPV on human cervical proteins.
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Cell Culture Unit
The Trust has provided funding to set up a new cell culture laboratory
at St Mary's Hospital. Our Patron, Wendy Turner Webster, opened
the new laboratory on 22 June 2001.
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Additional Research
The Trust has agreed to provide a one-year grant additional general
support to the work of Dr Hampson's established team all working
on the problem of cervical cancer.
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The Humane Research Trust Laboratory
University
of East Anglia, Norwich
Dr Michael Wormstone
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The Eye Research Group at the ARVO meeting (Left to Right): Julie Sanderson, Julie Eldred, David Broadway, Lucy Dawes, Jeremy Rhodes, Michael Wormstone, Nuwan Niyadurupola, Pauline Radreau, Peter Sidaway, Sarah Russell
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The Trust's Laboratory at the University of East
Anglia is dedicated entirely to non-animal techniques and is a world
leader in research into cataract and other eye diseases.
The Trusts' Grant programme at the Laboratory
embraces many areas:-
- Cataract Research - Dr Michael Wormstone.
This project has investigated the secondary lens cell growth, which
occurs after cataract surgery, studying the factors that influence
the growth and ways in which it can be inhibited. The team is now
exploring ways of delivering new treatments to lens implants. We
are delighted to acknowledge the generous assistance of the Community
Fund in funding this project.
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Dr Michael Wormstone
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Human Tissue Lectureship. The Trust has agreed to fund the first
five years of a Lectureship in Human Tissue Technology, which will
be held by Dr Wormstone. This will enable Dr Wormstone to pass on
to a new generation of researchers the expertise he has gained in
human tissue techniques. After the Trust's initial guarantee period,
the University will take on the commitment, so the Lectureship will
be a permanent appointment.
- The Trust provides annual grant support, which funds Postgraduate
Studentships teaching human techniques as well as helping with the
work of the laboratory generally.
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A New model To Study Infammatory Signals For Barrett's Oesphagus
University of East Anglia, Norwich
Dr Mark Williams
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The very first images of a human Barrett’s crypt maintained in a novel three-dimensional culture system. Cell nuclei are labelled red and proliferating cells are labelled yellow.
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A collaborative research project between the Gastrointestinal Research Laboratory at the University of East Anglia and clinicians at the Norfolk and Norwich University Hospital will develop a new model to study inflammatory signals for Barrett’s Oesophagus. The oesophagus is more commonly known as the food pipe or gullet and is the tube that carries food from your mouth to your stomach. Over the last 30 years oesophageal cancer has become more prevalent and is now the 9th commonest cancer in the UK. There are nearly 8000 new cases diagnosed in the UK each year and the prognosis for this disease is very poor with a mortality rate of 80% (only 10% of sufferers survive for 5 years or more). Risk factors for oesophageal cancer include age, gender (more common in males), smoking, alcohol and a diet low in fruit and vegetables. Also, people with a condition called Barrett’s oesophagus are up to 125 times more likely to develop oesophageal cancer. Barrett’s oesophagus is thought to develop following long-term acid indigestion (reflux) from the stomach which gives rise to chronic inflammation. In the case of Barrett’s sufferers, the lining of the oesophagus heals itself by replacing the damaged multi-layered lining of the lower oesophagus with a mass of disorganised tubular structures called crypts. It is therefore imperative that the molecular and cellular basis by which inflammatory mediators promote Barrett’s oesophagus and progression to cancer is understood better in order that preventative measures can be deployed following diagnosis at endoscopy. Hitherto, the study of Barrett’s oesophagus has been hampered by the lack of an ex vivo human tissue model of the disease. The Humane Research Trust is funding Miss Natalia Scobioala-Laker in the Gastrointestinal Laboratory to conduct a three year PhD programme of research during which time she will place human tissue samples of Barrett’s oesophagus into a novel three-dimensional tissue-culture system. Natalia will apply state-of-the-art fluorescence imaging technologies to identify the inflammatory factors that promote propagation of Barrett’s oesophagus and progression to oesophageal cancer.
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PhD Student Anne Bielemeier & Dr Lindsay Marshall |
Cystic Fibrosis
Aston University - Dr Lindsay Marshall
The aims of our research project are simple, achievable and of vital importance in the quest to develop effective treatments for people with CF(Cystic Fibrosis). We aim to develop accurate models of human airways in the laboratory to use for testing potential therapeutics. We also plan to use our cell culture techniques to generate a valid model of the CF airways in the laboratory so that we can mimic the infections typically observed in people with CF. We will use human cells grown under appropriate conditions which allow the cells to develop the features and, importantly, the functions that they perform normally in people. Currently, mice artificially manipulated to express the faulty CF gene are used for this type of study but we don’t feel that this is a suitable model, and this is supported by reports that indicate these manipulated mice do not get the same lung disease as people with CF.
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Neurotoxicity Testing
Aston University, Birmingham
Dr Michael Coleman
Trust Funded Postgraduate Studentship
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Dr Michael Coleman
and Thomas Zilz from Aston University
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The human central nervous system is acutely vulnerable
to damage from a number of drugs and chemicals, but there is at present
no in vitro test that can model the full range of potential
threats which might arise. Some tests reveal toxicity by assessing
the ability of a human cell line to carry our basic functions in the
presence of the toxic agent, but toxicity can arise at a much later
stage as a result of the way the body processes the original substance.
This project aims to produce a human-tissue based model that will enable
these problems to be studied in the laboratory without the use of animals.
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Towards a Non-Animal Model for Testing New Drugs Against Parasites
Dr David Timson, Queens' University, Belfast
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PhD Student Mark O'Shea and Dr David Timson |
Parasitic worm infections affect millions of humans and farm animals worldwide. One parasite of particular importance is the liver fluke, which infects an estimated 17 million humans, mostly in the developing world and causes billions of pounds worth of economic losses within the global agricultural industry. Infection with liver fluke results in pain, poor growth and, in some cases, death. Treating these infections is therefore a public health issue in the developing world and is crucial in the improvement of both agriculture and animal welfare.
The current preferred treatment against this parasite is a drug called triclabendazole. This is a safe and effective drug that can be used in both humans and animals. Unfortunately, just as bacteria such as MRSA have become resistant to antibiotics, there are now widespread reports of liver flukes displaying resistance to triclabendazole. Therefore there is now an urgent need for the development of new treatments to combat the liver fluke parasite.
An effective treatment must be successful in killing the parasite while not harming the mammalian host. Current methods used for investigating the action of anti-fluke drugs involve the parasites’ exposure to the drug and observing the responses. Unfortunately the only known way to produce live adult flukes is to grow them within a mammalian host, such as a rat, which must then be killed in order to extract the parasite.
Funded by The Humane Research Trust, Mark O’Shea has just commenced a PhD project, with Dr David Timson at Queen’s University Belfast. Mark is researching alternate methods to test certain groups of compounds. He is ideally qualified for this having a BSc in Pharmacology and an MSc in Molecular Parasitology from the University of Liverpool. Mark will identify the genes coding for calcium channel proteins. These are an important group of proteins as they regulate and control the entry and movement of calcium ions with the cell. Generally, if they go wrong, the cell will die therefore providing an attractive target for a wide variety of compounds. Once Mark has identified the genes, he will insert them into baker’s yeast (in place of the yeast’s own calcium channel genes). This will provide a model for testing compounds for their effectiveness against liver fluke ion channels. By subjecting the yeast to a series of biochemical tests for calcium channel activity it should be possible to quantify and rank the potency of the various compounds. In addition to saving animals, the new method should be cheaper, faster and more quantitative than existing ones.
In the long term it is hoped that it will be possible to construct similar model systems for other ion channels, both from the liver fluke and other parasitic worms.
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Tetraspanins
University of Sheffield
Dr Peter Monk
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PhD Student Marzieh Fanaei |
Tetraspanins are a group of proteins found on the surface of cells including human cells. They have been linked to several human diseases including cancer, Hepatitis C and HIV-1 infection but little is known about their function. To date, tetraspanins have been studied using genetically-manipulated mice and also antibodies generated in animals. To get around the issues associated with these methods, we aim to make a set of research tools for studying tetraspanin proteins using bacteria instead of animals.
The first step is to make the most important part of the protein, the EC2, for each tetraspanin (see figure). So far, EC2s have been made for only 8 out of the 33 tetraspanins. EC2s are excellent tools for research, for example we have already shown that some EC2s can prevent HIV infection of white blood cells and Hepatitis C infection of liver cells. They can also be used in a process called ‘phage display’ to select desired antibodies against each tetraspanin, without using animals.
The tools that we make as part of this project will be sent to researchers worldwide to investigate different aspects of tetraspanin function. Research in our own lab has recently focused on the role of tetraspanins in the formation of cells involved in bone erosion. Bone erosion occurs in diseases like osteoporosis and arthritis. The use of EC2s will enable us to study and understand how tetraspanins affect bone erosion and hopefully lead to new therapies.
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Novel Effector of Cell Death Studied in an Eye Cancer Experimental Model
Dr Luminita Paraoan, University of Liverpool
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Dr Luminita Paraoan and Dr Lyndsay Davies (post-doctoral researcher funded by The Humane Research Trust) in the Ocular Molecular Biology Laboratory at the University of Liverpool |
Funding from The Humane Research Trust is enabling a new line of research into mechanisms controlling the fine balance between cell death and survival. The research is undertaken in the Ophthalmology Research Unit, University of Liverpool making use of specific eye cells as an experimental model of a cell death pathway that plays a role in cancer development.
Cells have an in-built mechanism, called programmed cell death or apoptosis, which dictates their own death. This method of self-destruction safely removes cells from the body and is critical for reducing the number of cells when needed, for removing worn-out or aged cells or for eliminating damaged cells and thus preventing cells with defects from multiplying and limiting further damage that can lead to uncontrolled cell growth and the development of cancer. In cancer, the mechanism of apoptosis is often faulty, frequently due to mutations or loss of genes that normally function to promote cell death. This also makes cancer cells more difficult to destroy, since many anti-cancer drugs and treatments work by promoting the diseased cells to undergo cell death. Consequently, cancer cells which cannot engage in this process are often resistant to these drugs.
Apoptosis is a highly organised and tightly controlled method of cell death that involves the interaction and association of many different proteins and molecules. Removal or modification of just one of these components can lead to disruption of this complex process. We are investigating the role played by a gene called PERP (abbreviated from p53-apoptosis effector related to PMP-22) recently shown by us to control the death of cells in a type of eye cancer. Specifically, PERP occurs at much lower levels in the aggressive (compared with the less aggressive) type of uveal melanoma (UM) that spreads to other parts of the body, leading to a high mortality rate. In addition, PERP is also involved in maintaining contacts between cells. Loss of such cell-cell contacts is implicated in the spread of cancer cells to other parts of the body. Consequently, the lack of PERP may cause the inability of abnormal cells to be removed, as well as possibly mobilising them, thus contributing to the progression of the cancer.
We have identified five established and well characterized HUMAN UM cell lines, originally derived from primary UM tumours, that represent a reliable experimental model for investigating the activation, mechanism of action and regulation of PERP in both cell death and cell adhesion. These cell lines also display distinct features allowing vitally important questions regarding the role of PERP in cancer formation and progression to be addressed in cells with different levels of aggressiveness. To date, the involvement of PERP in such processes has relied heavily on the use of animal models and animal-derived tissues. Our in vitro experimental model is highly amenable to the experimental manipulation that is required for dissecting such complex biological mechanisms. We are particularly interested in studying the effect that different levels of PERP have on the ability of cells to undergo cell death and on their response to inducers of apoptosis, some of which are considered potential therapeutic agents. In addition, whereas animal models have been used extensively for investigating the capacity of UM cells to invade other tissues, we will use an in vitro approach to study the effect of PERP on the invasive properties of UM cells and establish whether low PERP levels contribute to their levels of aggressiveness. These findings may have implications for other cancer types which have reported an association between low PERP levels and aggressive tumours.
In the long term, we believe that our investigations into the role and regulation of PERP will provide further understanding of how the decision between the life and death of a cell is made, and so lead to the development of better treatments.
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